DIHYDRO-2H-BENZO[b][1,4]OXAZINE SULFONAMIDE AND RELATED COMPOUNDS FOR USE AS AGONISTS OF RORy AND THE TREATEMENT OF DISEASE

ABSTRACT

The invention provides dihydro-2H-benzo[b] [1,4]oxazine sulfonamide and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 62/157,224, filed May 5, 2015, and U.S.Provisional Patent Application Ser. No. 62/210,076, filed Aug. 26, 2015,the contents of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides dihydro-2H-benzo[b][1,4]oxazine sulfonamide andrelated compounds, methods of promoting RORγ activity and/or increasingthe amount of IL-17 in a subject, and therapeutic uses of thedihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds, suchas treating medical conditions in which activation of immune response isbeneficial.

BACKGROUND

Retinoid-related orphan receptors (ROR) are reported to have animportant role in numerous biological processes. See, for example,Dussault et al. in Mech. Dev. (1998) vol. 70, 147-153; and Andre et al.in EMBO J. (1998) vol. 17, 3867-3877. Scientific investigations relatingto each of retinoid-related orphan receptors RORα, RORβ, and RORγ havebeen described in the literature. See, for example, Hirose et al. inBiochem. Biophys. Res. Commun. (1994) vol. 205, 1976-1983; Giguere etal. in Genes. Dev. (1994) vol. 8, 538-553; Medvedev et al. in Gene(1996) vol. 181, 199-206; Ortiz et al. in Mol. Endocrinol. (1995) vol.9, 1679-1691; and A. M. Jetten in Curr Drug Targets Inflamm Allergy(2004) vol. 3, 395-412). Continuing research in this field is spurred bythe promise of developing new therapeutic agents to treat medicaldisorders associated with retinoid-related orphan receptor activity.

RORγ has been reported to be expressed in high concentration in varioustissues, such as thymus, kidney, liver, muscle, and certain fat tissue.See, for example, Hirose et al. in Biochem. Biophys. Res. Commun. (1994)vol. 205, 1976-1983; Medvedev et al. in Gene (1996) vol. 181, 199-206;Ortiz et al. in Mol. Endocrinol. (1995) vol. 9, 1679-1691; and He et al.in Immunity (1998) vol. 9, 797-806. Two isoforms of RORγ have beenidentified and are referred to as γ1 and γ2 (also referred to as RORγt).See, for example, He et al. in Immunity (1998) vol. 9, 797-806.Expression of the γ2 isoform has been reported to appear in, forexample, double-positive thymocytes. See, for example, He et al. inImmunity (1998) vol. 9, 797-806; and Villey et al. in Eur. J. Immunol.(1999) vol. 29, 4072-4080. RORγt plays a critical role in regulatingdifferentiation of Th17 cells, a subset of T helper lymphocytes. See,for example, Ivanov et al. in Cell (2006) vol. 126, 1121-1133. Th17cells are important for recruiting tumor-killing cytotoxic CD8+ T cellsand natural killer cells into the tumor microenvironment. The level ofTh17 cells correlated positively with patient survival or slower diseaseprogression in certain cancers. See, for example, Kryczek et al. inBlood (2009) vol 114, 1141-1149; and Sfanos et al. in Clinical CancerResearch (2008) vol 14, 3254-3261. Compounds capable of enhancing RORγtactivity are thus contemplated to provide a therapeutic benefit in thetreatment of cancer.

Cancer continues to be a significant health problem despite thesubstantial research efforts and scientific advances reported in theliterature for treating this disease. Some of the most frequentlydiagnosed cancers include prostate cancer, breast cancer, and lungcancer. Prostate cancer is the most common form of cancer in men. Breastcancer remains a leading cause of death in women. Current treatmentoptions for these cancers are not effective for all patients and/or canhave substantial adverse side effects.

Accordingly, a need exists for improved treatments for cancer. Thepresent invention addresses this need and provides other relatedadvantages.

SUMMARY

The invention provides dihydro-2H-benzo[b][1,4]oxazine and relatedcompounds, pharmaceutical compositions, methods of promoting RORγactivity and/or increasing the amount of IL-17 in a subject, and methodsof treating various medical disorders using such compounds. Inparticular, one aspect of the invention provides a collection ofdihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds, suchas a compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined in the detailed description. Another aspect of the inventionprovides a collection of compounds represented by Formula II:

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined in the detailed description. Further description ofadditional collections of dihydro-2H-benzo[b][1,4]oxazine sulfonamideand related compounds are described in the detailed description.

Another aspect of the invention provides a method of treating a subjectsuffering from a medical disorder. The method comprises administering tothe subject a therapeutically effective amount of one or moredihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compoundsdescribed herein, e.g., a compound of Formula I, I-A, I-B, II, II-A,II-B, or II-C. A large number of disorders can be treated using thedihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compoundsdescribed herein. For example, the compounds described herein can beused to treat cancer, a bacterial infection, a fungal infection, or animmune deficiency disorder.

Another aspect of the invention provides a method of promoting theactivity of RORγ. The method comprises exposing a RORγ to an effectiveamount of one or more dihydro-2H-benzo[b][1,4]oxazine sulfonamide orrelated compounds described herein, e.g., a compound of Formula I, I-A,I-B, II, II-A, II-B, or II-C, or a pharmaceutical composition describedherein.

Another aspect of the invention provides a method of increasing theamount of IL-17 in a subject. The method comprises administering to asubject an effective amount of one or moredihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compoundsdescribed herein, e.g., a compound of Formula I, I-A, I-B, II, II-A,II-B, or II-C, or a pharmaceutical composition described herein, toincrease the amount of IL-17 in the subject.

DETAILED DESCRIPTION

The invention provides dihydro-2H-benzo[b][1,4]oxazine sulfonamide andrelated compounds, pharmaceutical compositions, methods of promotingRORγ activity and/or increasing the amount of IL-17 in a subject, andtherapeutic uses of the dihydro-2H-benzo[b][1,4]oxazine sulfonamide andrelated compounds. The practice of the present invention employs, unlessotherwise indicated, conventional techniques of organic chemistry,pharmacology, molecular biology (including recombinant techniques), cellbiology, biochemistry, and immunology. Such techniques are explained inthe literature, such as in “Comprehensive Organic Synthesis” (B. M.Trost & I. Fleming, eds., 1991-1992); “Handbook of experimentalimmunology” (D. M. Weir & C. C. Blackwell, eds.); “Current protocols inmolecular biology” (F. M. Ausubel et al., eds., 1987, and periodicupdates); and “Current protocols in immunology” (J. E. Coligan et al.,eds., 1991), each of which is herein incorporated by reference in itsentirety.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section. Further, when avariable is not accompanied by a definition, the previous definition ofthe variable controls.

Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name, and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “—O-alkyl” etc.

The term “alkyl” refers to a saturated straight or branched hydrocarbon,such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms,referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, etc.

The term “alkylene” refers to a diradical of an alkyl group. Exemplaryalkylene groups include —CH₂—, —CH₂CH₂—, and —CH₂C(H)(CH₃)CH₂—. The term“—(C₀ alkylene)-” refers to a bond. Accordingly, the term “—(C₀₋₃alkylene)-” encompasses a bond (i.e., C₀) and a —(C₁₋₃ alkylene) group.

The term “heteroalkylene” refers to an alkylene group in which one ormore carbon atoms has been replaced by a heteroatom (e.g., N, O, or S).Exemplary heteroalkylene groups include —CH₂O—, —CH₂OCH₂—, and—CH₂CH₂O—. The heteroalkylene group may contain, for example, from 2-4,2-6, or 2-8 atoms selected from the group consisting of carbon and aheteroatom (e.g., N, O, or S).

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₃-C₆ cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl,cyclopentyl, cyclobutyl, and cyclopropyl.

The term “cycloalkylene” refers to a diradical of a cycloalkyl group.Exemplary cycloalkylene groups include

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. Exemplary haloalkyl groups include —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CF₂CF₃, and the like. The term “fluoroalkyl” refers toan alkyl group that is substituted with at least one fluorine atom.

The term “hydroxyalkyl” refers to an alkyl group that is substitutedwith at least one hydroxyl. Exemplary hydroxyalkyl groups include—CH₂CH₂OH, —C(H)(OH)CH₃, —CH₂C(H)(OH)CH₂CH₂OH, and the like.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Exemplary aralkyl groups include

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with, for example, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl,—CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido,sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic aromatic ring systems having two or more carbocyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein all of the fused rings are aromatic rings,e.g., in a naphthyl group.

The term “phenylene” refers to a multivalent radical (e.g., a divalentor trivalent radical) of benzene. To illustrate, a divalent valentradical of benzene is illustrated by the formula

The term “partially unsaturated bicyclic carbocyclyl” refers to abicyclic carbocyclic group that comprises at least one carbon-carbondouble bond between ring carbon atoms and at least one ring in thebicyclic carbocyclic group is not aromatic. Representative examples of apartially unsaturated bicyclic carbocyclyl include, for example:

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms (e.g., O, N,and S). Representative examples of heteroaryl groups include pyrrolyl,furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and thelike. Unless specified otherwise, the heteroaryl ring may be substitutedat one or more ring positions with, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. The term “heteroaryl” also includes polycyclicaromatic ring systems having two or more rings in which two or more ringatoms are common to two adjoining rings (the rings are “fused rings”)wherein all of the fused rings are heteroaromatic, e.g., in anaphthyridinyl group. In certain embodiments, the heteroaryl is a 5-6membered monocylic ring or a 9-10 membered bicyclic ring.

The term “heteroarylene” refers to a multi-valent (e.g., di-valent ortrivalent) aromatic group that comprises at least one ring heteroatom.An exemplary “heteroarylene” is pyridinylene, which is a multi-valentradical of pyridine. For example, a divalent radical of pyridine isillustrated by the formula

In certain embodiments, the “heteroarylene” is a divalant, 5-6 memberedheteroaromatic group containing 1, 2, or 3 ring heteroatoms (e.g., O, N,or S).

The terms ortho, meta, and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

As used herein, the terms “heterocyclic” and “heterocyclyl” represent,for example, an aromatic or nonaromatic ring (e.g., a monocyclic orbicyclic ring) containing one or more heteroatoms. The heteroatoms canbe the same or different from each other. Examples of heteratomsinclude, but are not limited to nitrogen, oxygen and sulfur. Aromaticand nonaromatic heterocyclic rings are well-known in the art. Somenonlimiting examples of aromatic heterocyclic rings include, but are notlimited to, pyridine, pyrimidine, indole, purine, quinoline andisoquinoline. Nonlimiting examples of nonaromatic heterocyclic compoundsinclude, but are not limited to, piperidine, piperazine, morpholine,pyrrolidine and pyrazolidine. Examples of oxygen containing heterocyclicrings include, but are not limited to, furan, oxirane, 2H-pyran,4H-pyran, 2H-chromene, benzofuran, and 2,3-dihydrobenzo[b][1,4]dioxine.Examples of sulfur-containing heterocyclic rings include, but are notlimited to, thiophene, benzothiophene, and parathiazine. Examples ofnitrogen containing rings include, but are not limited to, pyrrole,pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline,imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine,indole, purine, benzimidazole, quinoline, isoquinoline, triazole, andtriazine. Examples of heterocyclic rings containing two differentheteroatoms include, but are not limited to, phenothiazine, morpholine,parathiazine, oxazine, oxazole, thiazine, and thiazole. The heterocyclicring is optionally further substituted at one or more ring positionswith, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl, alkylthio,sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Incertain embodiments, the heterocyclyl group is a 3-7 membered ring that,unless specified otherwise, is substituted or unsubstituted.

The term “heterocycloalkyl” refers to a saturated heterocyclyl grouphaving, for example, 3-7 ring atoms (e.g., O, N, or S).

The term “heterocycloalkylene” refers to a multi-valent (e.g., di-valentor trivalent) saturated heterocyclyl group having, for example, 3-7 ringatoms. An exemplary “heterocycloalkylene” is piperidinylene, which is amulti-valent radical of piperidine. In certain embodiments, the“heterocycloalkylene” is a divalant, 5-6 membered saturated heterocyclylcontaining 1 or 2 ring heteroatoms (e.g., O, N, or S).

The term “partially unsaturated bicyclic heterocyclyl” refers to abicyclic heterocyclic group that comprises at least one double bondbetween two ring atoms and at least one ring in the bicyclicheterocyclic group is not aromatic. Representative examples of apartially unsaturated bicyclic heterocyclyl include, for example:

The term “partially unsaturated bicyclic oxo-heterocyclyl” refers to abicyclic heterocyclic group that comprises at least one double bondbetween ring atoms, one oxo substituent, and at least one ring in thebicyclic heterocyclic group is not aromatic. Representative examples ofa partially unsaturated bicyclic oxo-heterocyclyl include, for example:

The phrase “5-6 membered heterocyclic group containing at least oneunsaturated carbon atom in the ring” refers to a 5-6 memberedheterocyclic group containing at least one ring carbon atom where saidcarbon atom has a double bond to another atom, such as another atom inthe heterocyclic ring or to an exocyclic oxygen atom such that the ringcarbon atom is part of a C═O group. Exemplary 5-6 membered heterocyclicgroups containing at least one unsaturated carbon atom in the ringinclude, for example:

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(m)—R⁶¹, or R⁵⁰ and R⁵¹, taken togetherwith the N atom to which they are attached complete a heterocycle havingfrom 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In certain embodiments, only oneof R⁵⁰ or R⁵¹ may be a carbonyl, e.g., R⁵⁰, R⁵¹ and the nitrogentogether do not form an imide. In other embodiments, R⁵⁰ and R⁵¹ (andoptionally R⁵²) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, and—O—(CH₂)_(m)—R⁶¹, where m and R⁶¹ are described above.

The term “haloalkoxy” refers to an alkoxy group that is substituted withat least one halogen. Exemplary haloalkoxy groups include —OCH₂F,—OCHF₂, —OCF₃, —OCH₂CF₃, —OCF₂CF₃, and the like. The term“fluoroalkoxyl” refers to an alkoxy group substituted by at least onefluorine atom.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane substituted with an oxo group is cyclopentanone.

The symbol “

” indicates a point of attachment.

The term “substituted” means that one or more hydrogens on the atoms ofthe designated group are replaced with a selection from the indicatedgroup, provided that the atoms' normal valencies under the existingcircumstances are not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Theterms “stable compound’ or “stable structure” refer to a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When any substituent or variable occurs more than one time in anyconstituent or the compound of the invention, its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Nonlimiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. Further, certaincompounds described herein may be optically active. The presentinvention contemplates all such compounds, including cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. The compounds may containone or more stereogenic centers. For example, asymmetric carbon atomsmay be present in a substituent such as an alkyl group. All suchisomers, as well as mixtures thereof, are intended to be included inthis invention, such as, for example, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers, and it is intended thatall of the possible optical isomers, diastereomers in mixtures, and pureor partially purified compounds are included within the ambit of thisinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Alternatively, a particular enantiomer of a compound of the presentinvention may be prepared by asymmetric synthesis. Still further, wherethe molecule contains a basic functional group (such as amino) or anacidic functional group (such as carboxylic acid) diastereomeric saltsare formed with an appropriate optically-active acid or base, followedby resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. Chiral center(s) in a compound of the present inventioncan have the S or R configuration as defined by the IUPAC 1974Recommendations. Further, to the extent a compound described herein mayexist as a atropisomer (e.g., substituted biaryls), all forms of suchatropisomer are considered part of this invention.

As used herein, the terms “subject” and “patient” are usedinterchangeable and refer to organisms to be treated by the methods ofthe present invention. Such organisms preferably include, but are notlimited to, mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and most preferably includes humans.

The term “EC₅₀” is art-recognized and refers to the concentration of acompound that is required to achieve 50% of the maximum possibleactivation of the target.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results (e.g., atherapeutic, ameliorative, inhibitory or preventative result). Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate (also known astoluenesulfonate), undecanoate, and the like. Other examples of saltsinclude anions of the compounds of the present invention compounded witha suitable cation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group), and the like. Further examples of salts include, but arenot limited to: ascorbate, borate, nitrate, phosphate, salicylate, andsulfate. Further, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al., Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al., Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J of Pharmaceutics(1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference.

Additional exemplary basic salts include, but are not limited to:ammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as dicyclohexylamines, t-butyl amines, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chainhalides (e.g., decyl, lauryl, and stearyl chlorides, bromides andiodides), aralkyl halides (e.g., benzyl and phenethyl bromides), andothers.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

In addition, when a compound of the invention contains both a basicmoiety (such as, but not limited to, a pyridine or imidazole) and anacidic moiety (such as, but not limited to, a carboxylic acid)zwitterions (“inner salts”) may be formed. Such acidic and basic saltsused within the scope of the invention are pharmaceutically acceptable(i.e., non-toxic, physiologically acceptable) salts. Such salts of thecompounds of the invention may be formed, for example, by reacting acompound of the invention with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The present invention includes the compounds of the invention in alltheir isolated forms (such as any solvates, hydrates, stereoisomers, andtautomers thereof). Further, the invention includes compounds in whichone or more of the atoms may be artificially enriched in a particularisotope having the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number predominantly found innature. The present invention is meant to include all suitable isotopicvariations of the compounds of the invention. For example, differentisotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H).Protium is the predominant hydrogen isotope found in nature. Enrichingfor deuterium may afford certain therapeutic advantages, such asincreasing in vivo half-life or reducing dosage requirements, or mayprovide a compound useful as a standard for characterization ofbiological samples. Isotopically-enriched compounds can be preparedwithout undue experimentation by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theSchemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The abbreviation “THF” is art-recognized and refers to tetrahydrofuran.The abbreviation “DCM” is art-recognized and refers to dichloromethane.The abbreviation “DMF” is art-recognized and refers todimethylformamide. The abbreviation “DMA” is art-recognized and refersto dimethylacetamide. The abbreviation “EDTA” is art-recognized andrefers to ethylenediaminetetraacetic acid. The abbreviation “TFA” isart-recognized and refers to trifluoroacetic acid. The abbreviation “Ts”is art-recognized and refers to tosylate. The abbreviation “TBS” isart-recognized and refers to tert-butyldimethylsilyl. The abbreviation“DMSO” is art-recognized and refers to dimethylsulfoxide. Theabbreviation “Tf” is art-recognized and refers to triflate, ortrifluoromethylsulfonate. The abbreviation “Pin” is art-recognized andrefers to pinacolato.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified.

I. Dihydro-2H-benzo[b][1,4]oxazine Sulfonamide and Related Compounds

The invention provides dihydro-2H-benzo[b][1,4]oxazine sulfonamide andrelated compounds. Exemplary compounds are described in the followingsections, along with exemplary procedures for making the compounds.Additional exemplary compounds and synthetic procedures are described inthe Examples.

One aspect of the invention provides a compound represented by FormulaI:

or a pharmaceutically acceptable salt thereof; wherein:

A¹ is phenylene, 5-6 membered heteroarylene, or C₃₋₆heterocycloalkylene;

R¹ represents independently for each occurrence halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, or C₃₋₆ cycloalkyl;

R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 membered heteroalkylene)-A², —(C₀₋₃alkylene)-(C₃₋₆ cycloalkylene)-(C₀₋₃ alkylene)-A², —O-A², —N(R⁸)-A², or-A²; wherein A² is a 5-6 membered heterocyclic group containing at leastone unsaturated carbon atom in the ring and the heterocyclic group beingoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵);

R^(2B) represents independently for each occurrence C₁₋₆ alkyl or C₁₋₃haloalkyl;

R³ represents independently for each occurrence hydrogen, C₁₋₆haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —O—(C₁₋₆ alkylene)-OH, or —O—(C₁₋₆ alkylene)-CO₂R⁴; ortwo vicinal occurrences of R³ are taken together with intervening atomsto form a 4-6 membered ring;

R⁴ and R⁵ each represent independently for each occurrence hydrogen,C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attachedto the same nitrogen atom are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁶ and R⁷ each represent independently for each occurrence hydrogen orC₁₋₆ alkyl, or R⁶ and R⁷ are taken together with the carbon atom towhich they are attached to form a 3-6 membered carbocyclic ring; or R⁶and R^(2A) are taken together to form a bond;

R⁸ represents independently for each occurrence hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, or aralkyl;

R⁹ represents independently for each occurrence C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl;

X is one of the following:

-   -   (i) —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl,        —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆        alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆        alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl),        -(5-6 membered heterocycloalkylene)-phenyl, or —(C₃₋₆        cycloalkylene)-phenyl, each of which is optionally substituted        with 1, 2, or 3 substituents independently selected from the        group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;    -   (ii) —(C₂₋₆ alkenylene)-(C₃₋₆ cycloalkyl),

or an 8-10 membered, bicyclic partially saturated carbocyclyl, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturatedcarbocyclic or heterocyclic ring;

-   -   (iii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹        is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;        or    -   (iv) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;

Y is —C(R⁶)(R⁷)—, —O—, —C(O)—, or —S(O)_(p)—;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3.

In certain embodiments, A¹ is phenylene or 5-6 membered heteroarylene.

In certain embodiments R¹ represents independently for each occurrencehalogen or C₁₋₆ alkyl.

In certain embodiments, R³ represents independently for each occurrenceC₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or —O—(C₁₋₆alkylene)-OH. In certain embodiments, R³ is trifluoromethyl, fluoro,chloro, or methoxy. In certain embodiments, R³ is trifluoromethyl.

In certain embodiments, -A¹-(R³)_(n) is

In certain embodiments, -A¹-(R³)_(n) is one of the following:

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A². In certain embodiments,R^(2A) is —(C₂₋₃ alkylene)-O-A². In certain embodiments, R^(2A) is—O-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R^(2B) is methyl.

In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy. In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl,—(C₁₋₆ alkylene)-phenyl, or —(C₁₋₆ alkylene)-heteroaryl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —(C₂₋₆ alkenylene)-phenyl optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy.

In certain embodiments, X is —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆alkylene)-phenyl, each of which is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy. In certain embodiments, X is —O—(C₁₋₆ alkylene)-phenylor —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which is substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy, where at least one substituent is present at the orthoposition on the phenyl group in variable X. In certain embodiments, X is—O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each ofwhich is substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl or —N(R⁴)-aralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, X is —O-benzyl or—N(R⁴)-benzyl, each of which is substituted with 1 or 2 substituentsindependently selected from the group consisting of chloro, bromo, andfluoro.

In certain embodiments, Y is —C(R⁶)(R⁷)—. In certain embodiments, R⁶ andR⁷ are independently hydrogen or methyl.

In certain embodiments, Y is —C(R⁶)(R⁷)—, R⁶ and R⁷ are independentlyhydrogen or methyl, and X is attached at the 7-position of the1,2,3,4-tetrahydroquinolinyl ring.

In certain embodiments, Y is —O—. In certain embodiments, X is attachedat the 6-position of the 3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.

In certain embodiments, m is 0 or 1. In certain embodiments, p is 0. Incertain embodiments, p is 1.

The definitions of variables in Formula I above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii), e.g., such as where A is phenylene and R³ is selected from thegroup consisting of C₁₋₆ haloalkyl, halogen, hydroxyl, and C₁₋₆ alkyl.

Another aspect of the invention provides a compound represented byFormula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is phenylene or a 5-6 membered heteroarylene;

R¹ represents independently for each occurrence halogen, C₁₋₆ alkyl, orC₃₋₆ cycloalkyl;

R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 membered heteroalkylene)-A², or—O-A²; wherein A² is a 5-6 membered heterocyclic group containing atleast one unsaturated carbon atom and the heterocyclic group beingoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵);

R^(2B) represents independently for each occurrence C₁₋₆ alkyl or C₁₋₃haloalkyl;

R³ represents independently for each occurrence hydrogen, C₁₋₆haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, or —O—(C₁₋₆ alkylene)-OH; or two vicinal occurrences ofR³ are taken together with intervening atoms to form a 4-6 memberedring;

R⁴ and R⁵ each represent independently for each occurrence hydrogen,C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attachedto the same nitrogen atom are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁶ and R⁷ each represent independently for each occurrence hydrogen orC₁₋₆ alkyl, or R⁶ and R⁷ are taken together with the carbon atom towhich they are attached to form a 3-6 membered carbocyclic ring;

R⁸ represents independently for each occurrence hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, or aralkyl;

R⁹ represents independently for each occurrence C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl;

X is one of the following:

-   -   (i) —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl,        —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆        alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆        alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or        -(5-6 membered heterocycloalkylene)-phenyl, each of which is        optionally substituted with 1, 2, or 3 substituents        independently selected from the group consisting of halogen,        C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and        C₁₋₆ haloalkoxy;    -   (ii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹ is        —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl),        —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or    -   (iii) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl,        —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or        —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is        optionally substituted with 1, 2, or 3 substituents        independently selected from the group consisting of halogen,        C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and        C₁₋₆ haloalkoxy;

Y is —C(R⁶)(R⁷)—, —O—, or —C(O)—;

m and p are independently 0, 1, or 2; and

n is 1, 2, or 3.

In certain embodiments, A¹ is phenylene. In certain embodiments, A¹ is a5-6 membered heteroarylene.

In certain embodiments, n is 1. In certain embodiments, n is 1 or 2.

In certain embodiments, R³ represents independently for each occurrenceC₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or —O—(C₁₋₆alkylene)-OH. In certain embodiments, R³ is trifluoromethyl, fluoro,chloro, or methoxy. In certain embodiments, R³ is trifluoromethyl.

In certain embodiments, -A¹-(R³)_(n) is

In certain embodiments, -A¹-(R³)_(n) is one of the following:

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A². In certain embodiments,R^(2A) is —(C₂₋₃ alkylene)-O-A². In certain embodiments, R^(2A) is—O-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R^(2B) is methyl.

In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy. In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl,—(C₁₋₆ alkylene)-phenyl, or —(C₁₋₆ alkylene)-heteroaryl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —(C₂₋₆ alkenylene)-phenyl optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy.

In certain embodiments, X is —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆alkylene)-phenyl, each of which is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy. In certain embodiments, X is —O—(C₁₋₆ alkylene)-phenylor —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which is substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy, where at least one substituent is present at the orthoposition on the phenyl group in variable X. In certain embodiments, X is—O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each ofwhich is substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl or —N(R⁴)-aralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, X is —O-benzyl or—N(R⁴)-benzyl, each of which is substituted with 1 or 2 substituentsindependently selected from the group consisting of chloro, bromo, andfluoro.

In certain embodiments, Y is —C(R⁶)(R⁷)—. In certain embodiments, R⁶ andR⁷ are independently hydrogen or methyl.

In certain embodiments, Y is —C(R⁶)(R⁷)—, R⁶ and R⁷ are independentlyhydrogen or methyl, and X is attached at the 7-position of the1,2,3,4-tetrahydroquinolinyl ring.

In certain embodiments, Y is —O—. In certain embodiments, X is attachedat the 6-position of the 3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.

In certain embodiments, m is 0 or 1. In certain embodiments, p is 0. Incertain embodiments, p is 1.

The definitions of variables in Formula I-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii), e.g., such as where A is phenylene and R³ is selected from thegroup consisting of C₁₋₆ haloalkyl, halogen, hydroxyl, and C₁₋₆ alkyl.

Another aspect of the invention provides a compound represented byFormula I-B:

or a pharmaceutically acceptable salt thereof; wherein:

A¹ is phenylene or pyridinylene;

R¹ represents independently for each occurrence halogen, methyl, ethyl,or cyclopropyl;

R^(2A) is —(C₁₋₆ alkylene)-A² or -(2-6 membered heteroalkylene)-A²;wherein A² is a 5-6 membered heterocyclic group containing at least oneunsaturated carbon atom and the heterocyclic group being optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, and —CO₂R⁸;

R^(2B) is methyl or ethyl;

R³ represents independently for each occurrence C₁₋₃ haloalkyl, halogen,C₁₋₃ alkyl, or —O—(C₁₋₆ hydroxyalkyl);

R⁴ and R⁵ each represent independently for each occurrence hydrogen ormethyl; or an occurrence of R⁴ and R⁵ attached to the same nitrogen atomare taken together with the nitrogen atom to which they are attached toform a 3-7 membered heterocyclic ring;

R⁸ represents independently for each occurrence hydrogen or C₁₋₆ alkyl;

X is —(C₂₋₆ alkenylene)-phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy;

m and p are independently 0 or 1; and

n is 1 or 2.

In certain embodiments, A¹ is phenylene. In certain other embodiments,A¹ is pyridinylene.

In certain embodiments, R¹ is fluoro or methyl.

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A². In certain embodiments,R^(2A) is further selected from —O-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R³ represents independently for each occurrencetrifluoromethyl, halogen, or —O—(C₁₋₆ hydroxyalkyl).

In certain embodiments, R⁴ and R⁵ are taken together with the nitrogenatom to which they are attached to form a 3-7 membered heterocyclicring. In certain other embodiments, R⁴ and R⁵ each representindependently for each occurrence hydrogen or C₁₋₆ alkyl.

In certain embodiments, R⁸ is hydrogen

In certain embodiments, X is —(C₂₋₄ alkenylene)-phenyl substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen and C₁₋₆ haloalkyl. In certain embodiments, X is —(C₂₋₄alkenylene)-phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of chloro, fluoro, andtrifluoromethyl. In certain embodiments, X is —(C₂₋₄ alkenylene)-phenylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of chloro, fluoro, and trifluoromethyl, and saidsubstituents are located at the ortho positions of the phenyl group.

In certain embodiments, m and p are independently 0. In certainembodiments, n is 1.

The definitions of variables in Formula I-B above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii).

Another aspect of the invention provides a compound represented byFormula I-C:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is phenylene or pyrazolylene;

R^(2A) is -(2-6 membered heteroalkylene)-A²; wherein A² is a 5-6membered heterocyclic group containing at least one unsaturated carbonatom and the heterocyclic group being optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofC₁₋₃ alkyl, C₁₋₃ fluoroalkyl, chloro, fluoro, and oxo;

R³ represents independently for each occurrence C₁₋₂ fluoroalkyl,chloro, fluoro, cyclopropyl, C₁₋₃ alkyl, C₁₋₂ alkoxy, or C₁₋₂fluoroalkoxy;

X is —(C₂₋₆ alkenylene)-phenyl wherein the phenyl is substituted with 1,2, or 3 substituents independently selected from the group consisting ofchloro, fluoro, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, and C₁₋₂ fluoroalkoxy;

n is 1 or 2.

In certain embodiments, A¹ is phenylene. In certain embodiments, A¹ isphenylene; and R³ represents independently for each occurrence C₁₋₂fluoroalkyl, chloro, fluoro, C₁₋₂ alkoxy, or C₁₋₂ fluoroalkoxy.

In certain embodiments, A¹-(R³)_(n) is

In certain embodiments, R^(2A) is (C₂₋₃ alkylene)-O-A². In certainembodiments, R^(2A) is —(CH₂)₂-O-A².

In certain embodiments, R³ represents independently for each occurrenceC₁₋₂ fluoroalkyl, chloro, fluoro, C₁₋₂ alkoxy, or C₁₋₂ fluoroalkoxy. Incertain embodiments, R³ represents independently for each occurrenceC₁₋₂ fluoroalkyl, chloro, or fluoro. In certain embodiments, R³ is —CF₃.

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom. In certain embodiments, A² is a 5-6membered heterocyclic group containing at least one ring carbon atomsubstituted by oxo and the heterocyclic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, chloro, and fluoro. Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, chloro, andfluoro. In certain embodiments, the heterocyclic group in A² is a5-membered heterocyclic group. In certain embodiments, A² is imidazolyl;pyrazolyl; 1,2,3-triazolyl; tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl;1,3,4-oxadiazol-2(3H)-onyl; 1,3-dihydro-2H-imidazol-2-onyl; or2,4-dihydro-3H-1,2,4-triazol-3-onyl; each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, chloro, and fluoro.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₃ alkyl and C₁₋₃fluoroalkyl.

In certain embodiments, A² is H

In certain embodiments, X is —(C₂₋₄ alkenylene)-phenyl wherein thephenyl is substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of chloro, fluoro, C₁₋₂ fluoroalkyl.In certain embodiments, X is —(C₂₋₄ alkenylene)-phenyl wherein thephenyl is substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of chloro, fluoro, andtrifluoromethyl. In certain embodiments, X is —(C₂₋₄ alkenylene)-phenylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of chloro, fluoro, and trifluoromethyl, and saidsubstituents are located at the ortho positions of the phenyl group. Incertain embodiments, X is —(C(H)═C(CH₃))-phenyl substituted with 1 or 2substituents independently selected from the group consisting of chloro,fluoro, and trifluoromethyl, and said substituents are located at theortho positions of the phenyl group.

The definitions of variables in Formula I-C above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii).

In certain other embodiments, the compound is a compound defined by oneof the following formulae where variables X and Z are as defined inTable 1, or a pharmaceutically acceptable salt thereof.

TABLE 1 No. X Z I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

Another aspect of the invention provides a compound represented byFormula II:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is phenyl, 5-6 membered heteroaryl, or C₃₋₆ heterocycloalkyl;

R¹ represents independently for each occurrence halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, or C₃₋₆ cycloalkyl;

R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 membered heteroalkylene)-A², —(C₀₋₃alkylene)-(C₃₋₆ cycloalkylene)-(C₀₋₃ alkylene)-A², —O-A², —N(R⁸)-A², or-A²; wherein A² is a 5-6 membered heterocyclic group containing at leastone unsaturated carbon atom and the heterocyclic group being optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵);

R^(2B) represents independently for each occurrence C₁₋₆ alkyl or C₁₋₃haloalkyl;

R^(2C) is hydrogen or C₁₋₆ alkyl;

R³ represents independently for each occurrence hydrogen, C₁₋₆haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —O—(C₁₋₆ alkylene)-OH, or —O—(C₁₋₆ alkylene)-CO₂R⁴; ortwo vicinal occurrences of R³ are taken together with intervening atomsto form a 4-6 membered ring;

R⁴ and R⁵ each represent independently for each occurrence hydrogen,C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attachedto the same nitrogen atom are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁶ and R⁷ each represent independently for each occurrence hydrogen orC₁₋₆ alkyl, or R⁶ and R⁷ are taken together with the carbon atom towhich they are attached to form a 3-6 membered carbocyclic ring; or R⁶and R^(2A) are taken together to form a bond;

R⁸ represents independently for each occurrence hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, or aralkyl;

R⁹ represents independently for each occurrence C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl;

X is one of the following:

-   -   (i) —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl,        —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆        alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆        alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl),        -(5-6 membered heterocycloalkylene)-phenyl, or —(C₃₋₆        cycloalkylene)-phenyl, each of which is optionally substituted        with 1, 2, or 3 substituents independently selected from the        group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;    -   (ii) —(C₂₋₆ alkenylene)-(C₃₋₆ cycloalkyl),

or an 8-10 membered, bicyclic partially saturated carbocyclyl, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturatedcarbocyclic or heterocyclic ring;

-   -   (iii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹        is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;        or    -   (iv) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;

Y is —C(R⁶)(R⁷)—, —O—, —C(O)—, or —S(O)_(p)—;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 0, 1, 2, or 3.

In certain embodiments, A¹ is phenylene or 5-6 membered heteroarylene.

In certain embodiments R¹ represents independently for each occurrencehalogen or C₁₋₆ alkyl.

In certain embodiments, R³ represents independently for each occurrenceC₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or —O—(C₁₋₆alkylene)-OH. In certain embodiments, R³ is trifluoromethyl, fluoro,chloro, or methoxy. In certain embodiments, R³ is trifluoromethyl.

In certain embodiments, -A¹-(R³)_(n) is

In certain embodiments, -A¹-(R³)_(n) is one of the following:

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A². In certain embodiments,R^(2A) is —(C₂₋₃ alkylene)-O-A². In certain embodiments, R^(2A) is—O-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R^(2B) is methyl.

In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy. In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl,—(C₁₋₆ alkylene)-phenyl, or —(C₁₋₆ alkylene)-heteroaryl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —(C₂₋₆ alkenylene)-phenyl optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy.

In certain embodiments, X is —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆alkylene)-phenyl, each of which is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy. In certain embodiments, X is —O—(C₁₋₆ alkylene)-phenylor —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which is substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy, where at least one substituent is present at the orthoposition on the phenyl group in variable X. In certain embodiments, X is—O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each ofwhich is substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl or —N(R⁴)-aralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, X is —O-benzyl or—N(R⁴)-benzyl, each of which is substituted with 1 or 2 substituentsindependently selected from the group consisting of chloro, bromo, andfluoro.

In certain embodiments, Y is —C(R⁶)(R⁷)—. In certain embodiments, R⁶ andR⁷ are independently hydrogen or methyl.

In certain embodiments, Y is —C(R⁶)(R⁷)—, R⁶ and R⁷ are independentlyhydrogen or methyl, and X is attached at the 7-position of the1,2,3,4-tetrahydroquinolinyl ring.

In certain embodiments, Y is —O—. In certain embodiments, X is attachedat the 6-position of the 3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.

In certain embodiments, m is 0 or 1. In certain embodiments, p is 0. Incertain embodiments, p is 1.

The definitions of variables in Formula II above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii), e.g., such as where A is phenylene and R³ is selected from thegroup consisting of C₁₋₆ haloalkyl, halogen, hydroxyl, and C₁₋₆ alkyl.

Another aspect of the invention provides a compound represented byFormula II-A:

or a pharmaceutically acceptable salt thereof; wherein:

A¹ is phenylene or a 5-6 membered heteroarylene;

R¹ represents independently for each occurrence halogen, C₁₋₆ alkyl, orC₃₋₆ cycloalkyl;

R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 membered heteroalkylene)-A², or—O-A²; wherein A² is a 5-6 membered heterocyclic group containing atleast one unsaturated carbon atom and the heterocyclic group beingoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵);

R^(2B) represents independently for each occurrence C₁₋₆ alkyl or C₁₋₃haloalkyl;

R^(2C) is hydrogen or C₁₋₆ alkyl;

R³ represents independently for each occurrence hydrogen, C₁₋₆haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, or —O—(C₁₋₆ alkylene)-OH; or two vicinal occurrences ofR³ are taken together with intervening atoms to form a 4-6 memberedring;

R⁴ and R⁵ each represent independently for each occurrence hydrogen,C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attachedto the same nitrogen atom are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁶ and R⁷ each represent independently for each occurrence hydrogen orC₁₋₆ alkyl, or R⁶ and R⁷ are taken together with the carbon atom towhich they are attached to form a 3-6 membered carbocyclic ring;

R⁸ represents independently for each occurrence hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, or aralkyl;

R⁹ represents independently for each occurrence C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl;

X is one of the following:

-   -   (i) —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl,        —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆        alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆        alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl),        -(5-6 membered heterocycloalkylene)-phenyl, or —(C₃₋₆        cycloalkylene)-phenyl, each of which is optionally substituted        with 1, 2, or 3 substituents independently selected from the        group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;    -   (ii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹ is        —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;        or    -   (iii) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,        —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆        alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),        —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated        bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆        cycloalkyl), each of which is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano;

Y is —C(R⁶)(R⁷)—, —O—, or —C(O)—;

m and p are independently 0, 1, or 2; and

n is 1, 2, or 3.

In certain embodiments, A¹ is phenylene. In certain embodiments, A¹ is a5-6 membered heteroarylene.

In certain embodiments, n is 1. In certain embodiments, n is 1 or 2.

In certain embodiments, R³ represents independently for each occurrenceC₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or —O—(C₁₋₆alkylene)-OH. In certain embodiments, R³ is trifluoromethyl, fluoro,chloro, or methoxy. In certain embodiments, R³ is trifluoromethyl.

In certain embodiments, -A¹-(R³)_(n) is

In certain embodiments, -A¹-(R³)_(n) is one of the following:

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A². In certain embodiments,R^(2A) is —(C₂₋₃ alkylene)-O-A². In certain embodiments, R^(2A) is—O-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R^(2B) is methyl.

In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy. In certain embodiments, X is —(C₂₋₆ alkenylene)-phenyl,—(C₁₋₆ alkylene)-phenyl, or —(C₁₋₆ alkylene)-heteroaryl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —(C₂₋₆ alkenylene)-phenyl optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy.

In certain embodiments, X is —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certainembodiments, X is —O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆alkylene)-phenyl, each of which is substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy. In certain embodiments, X is —O—(C₁₋₆ alkylene)-phenylor —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which is substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy, where at least one substituent is present at the orthoposition on the phenyl group in variable X. In certain embodiments, X is—O—(C₁₋₆ alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each ofwhich is substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, Xis —O-aralkyl or —N(R⁴)-aralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy. In certain embodiments, X is —O-benzyl or—N(R⁴)-benzyl, each of which is substituted with 1 or 2 substituentsindependently selected from the group consisting of chloro, bromo, andfluoro.

In certain embodiments, Y is —C(R⁶)(R⁷)—. In certain embodiments, R⁶ andR⁷ are independently hydrogen or methyl.

In certain embodiments, Y is —C(R⁶)(R⁷)—, R⁶ and R⁷ are independentlyhydrogen or methyl, and X is attached at the 7-position of the1,2,3,4-tetrahydronaphthalenyl ring.

In certain embodiments, Y is —O—. In certain embodiments, X is attachedat the 6-position of the chromanyl ring.

In certain embodiments, m is 0 or 1. In certain embodiments, p is 0. Incertain embodiments, p is 1.

The definitions of variables in Formula II-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii), e.g., such as where A is phenylene and R³ is selected from thegroup consisting of C₁₋₆ haloalkyl, halogen, hydroxyl, and C₁₋₆ alkyl.

Another aspect of the invention provides a compound represented byFormula II-B:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene or pyridinylene;

R¹ represents independently for each occurrence halogen, methyl, ethyl,or cyclopropyl;

R^(2A) is —(C₁₋₆ alkylene)-A² or -(2-6 membered heteroalkylene)-A²;wherein A² is a 5-6 membered heterocyclic group containing at least oneunsaturated carbon atom and the heterocyclic group being optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, and —CO₂R⁸;

R^(2B) is methyl or ethyl;

R³ represents independently for each occurrence C₁₋₃ haloalkyl, halogen,C₁₋₃ alkyl, or —O—(C₁₋₆ hydroxyalkyl);

R⁴ and R⁵ each represent independently for each occurrence hydrogen ormethyl; or an occurrence of R⁴ and R⁵ attached to the same nitrogen atomare taken together with the nitrogen atom to which they are attached toform a 3-7 membered heterocyclic ring;

R⁸ represents independently for each occurrence hydrogen or C₁₋₆ alkyl;

X is —(C₂₋₆ alkenylene)-phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy;

m and p are independently 0 or 1; and

n is 1 or 2.

In certain embodiments, A is phenylene. In certain other embodiments, Ais pyridinylene.

In certain embodiments, R¹ is fluoro or methyl.

In certain embodiments, R^(2A) is —(C₁₋₆ alkylene)-A². In certainembodiments, R^(2A) is —(C₂₋₃ alkylene)-A². In certain embodiments,R^(2A) is -(2-6 membered heteroalkylene)-A².

In certain embodiments, A² comprises at least two ring nitrogen atoms.In certain embodiments, A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.

In certain embodiments, A² is a 5-6 membered heterocyclic groupcontaining at least one ring carbon atom substituted by oxo and theheterocyclic group being optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). Incertain embodiments, A² is a 5-6 membered heterocyclic group containing(i) at least one ring carbon atom substituted by oxo and (ii) at leastone double bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵). In certain embodiments,the heterocyclic group in A² is a 5-membered heterocyclic group.

In certain embodiments, A² is a 5-6 membered heteroaromatic groupcomprising at least two ring nitrogen atoms, at least one unsaturatedcarbon atom in the ring, and the heteroaromatic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹),and —N(R⁴)(R⁵). In certain embodiments, the heteroaromatic group in A²is a 5-membered heteroaromatic group.

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is imidazolyl; pyrazolyl; 1,2,3-triazolyl;tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl;1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, and —CO₂R⁸.

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).

In certain embodiments, A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).

In certain embodiments, R³ represents independently for each occurrencetrifluoromethyl, halogen, or —O—(C₁₋₆ hydroxyalkyl).

In certain embodiments, R⁴ and R⁵ are taken together with the nitrogenatom to which they are attached to form a 3-7 membered heterocyclicring. In certain other embodiments, R⁴ and R⁵ each representindependently for each occurrence hydrogen or C₁₋₆ alkyl.

In certain embodiments, R⁸ is hydrogen.

In certain embodiments, X is —(C₂₋₄ alkenylene)-phenyl substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen and C₁₋₆ haloalkyl. In certain embodiments, X is —(C₂₋₄alkenylene)-phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of chloro, fluoro, andtrifluoromethyl. In certain embodiments, X is —(C₂₋₄ alkenylene)-phenylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of chloro, fluoro, and trifluoromethyl, and saidsubstituents are located at the ortho positions of the phenyl group.

In certain embodiments, m and p are independently 0. In certainembodiments, n is 1.

The definitions of variables in Formula II-B above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii).

In certain other embodiments, the compound is a compound defined by oneof the following formulae where variables X and Z are as defined inTable 2, or a pharmaceutically acceptable salt thereof.

TABLE 2 No. X Z II-1 

II-2 

II-3 

II-4 

II-5 

II-6 

II-7 

II-8 

II-9 

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

II-57

II-58

II-59

II-60

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

II-70

II-71

II-72

II-73

II-74

II-75

II-76

II-77

II-78

Methods for preparing compounds described herein are illustrated in thefollowing synthetic Schemes. The Schemes are given for the purpose ofillustrating the invention, and are not intended to limit the scope orspirit of the invention. Starting materials shown in the Schemes can beobtained from commercial sources or be prepared based on proceduresdescribed in the literature.

The synthetic route illustrated in Scheme 1 is a general method forpreparing substituted 1,2,3,4-tetrahydroquinoline compounds F and G.Reaction of aniline A with diethyl 2-(ethoxymethylene)malonate Bfollowed by thermally induced cyclization with acid affords thesubstituted ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate C. Treatmentof compound C with phosphoryl trichloride affords the ethyl4-chloroquinoline-3-carboxylate D. Reduction of compound D with boranein pyridine (or by transition metal-mediated hydrogenation) affords theethyl 1,2,3,4-tetrahydroquinoline-3-carboxylate E, which can be reactedwith a sulfonyl chloride or sulfamoyl chloride to provide thesubstituted sulfonamide-tetrahydroquinoline F. The ester group of F canbe hydrolyzed to afford the substituted1,2,3,4-tetrahydroquinoline-3-carboxylic acid G. Compound G can beobtained in enanteriomerically enriched form by chiral separationtechniques described in the literature for carboxylic acids.

The reaction procedures in Scheme 1 are contemplated to be amenable topreparing a wide variety of 3-substituted 1,2,3,4-tetrahydroquinolinecompounds having different substituents at the R, X, and 3-positions.For example, numerous substituted anilines are known in the literatureand/or are commercially available or readily prepared from nitroaromaticcompounds. Furthermore, if a functional group on a molecule would not beamenable to a reaction condition described in Scheme 1, it iscontemplated that the functional group can first be protected usingstandard protecting group chemistry and strategies, and then theprotecting group is removed after completing the desired synthetictransformation. See, for example, Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991, for further description of protecting chemistry and strategies.For example, if X is OMe, the methyl moiety can be removed from F withboron tribromide to afford a 6- or 7-hydroxytetrahydroquinoline. Theresulting compound can be subjected to either alkylation with halides orwith a Mitsunobu reaction to afford a wide variety of OR groups as X. Inother embodiments, the —OH may be converted to triflate and be subjectedto Pd-mediated catalyzed reactions to afford a wide variety of carbonlinked substituents. In certain other embodiments, the ester group incompound F can be converted to another functional group using standardfunctional group manipulation procedures known in the art. See, forexample, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming,eds., 1991-1992).

Scheme 2 illustrates an alternative general method for preparingsubstituted 1,2,3,4-tetrahydroquinoline compound F. Condensation of asubstituted 2-nitrobenzaldehyde A with diethyl malonate affordsα-β-unsaturated diester B. Reduction of B with sodium borohydrideaffords diester C. Reduction of the nitro moiety of C with eithermetal-mediated hydrogenation or dissolving metal reduction procedures(e.g., Zn/AcOH or Fe in HCl) affords2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate D. Selective reductionof the 2-keto moiety of D affords ethyl1,2,3,4-tetrahydroquinoline-3-carboxylate E. The ester group in E can beconverted into additional functional groups via the methodologydescribed above in connection with Scheme 1.

Scheme 3 illustrates a general method for preparing substituted(R)-2-alkyl-1-(aryl or heteroarylsulfonyl)-1,2-dihydroquinoline-3-carboxylic acids D. A tandemMichael-aldol dehydration of a substituted N-(2-formylphenyl)(aryl orheteroaryl)sulfonamide A with a 3-substituted acrylaldehyde B catalyzedby (S)-diphenylprolinol triethyl silyl ether (see, for example, W. Wanget al. in Org. Lett. 9: 965-968, 2007; and A. Cordova et al. in Adv.Synth. Catal. 349: 827-832, 2007) affords substituted(R)-2-alkyl-1-(aryl or heteroarylsulfonyl)-1,2-dihydroquinoline-3-carbaldehyde C. Oxidation (see, forexample, Y. K. Bae et al. in Synlett. 24: 1848-1850, 2013; and S. J.Williams et al. in WO 2011/047432) of the aldehyde in C affordssubstituted (R)-2-alkyl-1-(aryl or heteroarylsulfonyl)-1,2-dihydroquinoline-3-carboxylic acid D.

Scheme 4 illustrates a general method for preparing substituted(R)-(2-alkyl-1-(aryl or heteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl alcohol B. Reduction ofaldehydein compound A with sodium borohydride in the presence of cerium(III) chloride (see, for example, Y. Hamada et al. in Tetrahedron 64:11568-11579, 2008) yields compound B where R′ is hydrogen. Addition ofan alkyl magnesium or alkyl lithium halide in the presence of cerium(III) chloride affords the secondary alcohol B where R′ is a lower alkyl(i.e., C₁₋₆ alkyl).

Scheme 5 illustrates a general procedure for preparing substituted(R)-3-(2-alkyl-1-(aryl or heteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)propanoic acid D. Treatment ofallylic alcohol A with methane sulfonyl halide (or a tosyl halide ortriflic anhydride may be used to activate the hydroxyl group, andalternatively the hydroxyl group may be converted to an allylic halideby methods known in the literature) affords compound B where the allylichydroxyl is activated with a leaving group. When R′ is the same as R″,an ester of an appropriate substituted (or unsubstituted) acetic acid isconverted to an anion with an appropriate base (e.g., LDA, lithiumhexamethyldisilazide, etc.) and is alkylated with B to yield compound C.When R′ is not the same as R″, various chiral enolate chemistry methodsfrom the literature may be used to provide a chiral acid. For example,the anion of an acyloxazolidinone may be be utilized. Removal of thealkyl ester of the chiral auxiliary with an appropriate base (e.g.,potassium carbonate, lithium hydroxide in the presence of peroxide) oran acid (for tert-butyl esters) affords (R)-3-(2-alkyl-1-(aryl orheteroaryl sulfonyl)-1,2-dihydroquinolin-3-yl)propanoic acid D.

Scheme 6 illustrates a general procedure for preparing substituted(R)-(2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkylamines C and D.Mitsunobu reaction (see, for example, D. L. Hughes et al. in OrganicReactions 42: 1992) of allylic alcohol A with phthalamide affordssubstituted phthamide B. Treatment of compound B with hydrazine in anappropriate solvent (for example, ethanol or isopropanol; see, forexample, H. Itoh et al. in J. Org. Chem. 43: 2320, 1978) affords(R)-(2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkylamine C. Reductiveamination of the amine group in compound C (see, for example, C. A.Maryanoff et al. in J. Org. Chem. 61: 3849-3860, 1996) affords(R)-(2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkylamine D.

Scheme 7 illustrates a general procedure for preparing substituted(R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)amide B, substituted(R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)carbamate C,substituted (R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)urea D (orsubstituted (R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)thiourea),substituted (R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)sulfonamide E, andsubstituted (R)—N-((2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkyl)sulfamide F. Reactionof substituted (R)-(2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinolin-3-yl)alkylamine A with anappropriate base and an acyl halide affords amide B. Alternatively, acoupling agent (e.g., a carbodiimide, PyBOP, treatment of the acid witha chloroformate to make a mixed anhydride, etc.) may be utilized tocouple a wide variety of acids to form amide B. The amine A may also becoupled with a choroformate to afford compound C; with an isocyanate,carbamoyl choride, or isothiocyanate to afford D; with a sulfonyl halideto afford E; or with a sulfamoyl halide to afford F.

Scheme 8 illustrates a general method of preparing substitutedcis-3-substituted-2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline B. Hydrogenation of thesubstituted (R)-2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2-dihydroquinoline A prepared via the abovemethods in the presence of a catalyst affords the substitutedcis-3-substituted-2-alkyl-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline B. The choice of thecatalyst depends on the substituents X and R. In cases wheredehalogenation or reductive removal of benzylic heteroatom is not anissue, Pd or Pt on carbon may be utilized. In other cases, Rh and/or aheterogeneous catalyst which does not reduce these functionalities ismore appropriate per literature procedures for such reductions.

Scheme 9 illustrates an alternative general method to preparesubstituted 3-substituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline E. A tandem reactioncombining radical and ionic cyclization of halogenated aniline A and asubstituted acrylate B affords substituted 3,4-dihydroquinolin-2-one C(see, for example, N. Jiao et al. in Tetrahedron 65: 1982-1987, 2009).Reduction of the amide group in C with a hydride (e.g., a borane orlithium aluminum hydride) affords substituted1,2,3,4-tetrahydroquinoline D. Sulfonylation of D with a sulfonyl halideyields the substituted 3-substituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline E.

Scheme 10 illustrates an alternative general method to prepare chiralsubstituted 3-substituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinolines. Alkylation of anacylated oxazolidinedione B with 2-nitrobenzylic halide A affords withhigh diastereomeric excess the 3-arylpropionamide C. Reduction of C withdissolving metal conditions affords chiral substituted3,4-dihydroquinolin-2-one D which can be elaborated to the substituted3-substituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinolines E and F based onprocedures described above.

Scheme 11 illustrates an alternative general method of preparingsubstituted cis-2,3-disubstituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline E. Alkylation of(3-ketoester B with 2-nitrobenzylic halide A affords substituted2-(2-nitrobenzyl)-3-ketoester C. Reduction of C affords substitutedethyl cis-2-alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylate D (see, forexample, R. A. Bunce et al. in J. Heterocyclic Chem. 44: 1059-1064,2007). This material can be sulfonylated as described above to affordthe substituted cis-2,3-disubstituted-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinoline E.

Scheme 12 illustrates a general method of preparing chiral substituted1-(aryl or hetereoarylsulfonyl)-1,2,3,4-tetrahydroquinoline Esubstituted at the 3-position with an oxygen bearing group. Wittigreaction of 2-nitroaldehyde A forms α,β-unsaturated ester B, which issubjected to Os-catalyzed asymmetric dihydroxylation with the(DHQ)₂-PHAL ligand (see, for example, K. B. Sharpless et al. in Chem.Rev. 94: 2483-2547, 1994) followed by treatment of the diol with thionylchloride to form cyclic sulfite C (see, for example, K. B. Sharpless etal. in J. Am. Chem. Soc. 110: 7538-7539, 1988). Sulfite C undergoes aone-pot cobalt chloride catalyzed reductive cyclization with sodiumborohydride (see, for example, A. Sudalai et al. in Organic Letters 11:803-806, 2009) to form the substituted chiral3-hydroxy-1,2,3,4-tetrahydroquinoline D. This material is sulfonylatedas described above to afford chiral substituted 1-(aryl orhetereoarylsulfonyl)-3-hydroxy-1,2,3,4-tetrahydroquinoline E. Thependant hydroxyl may be alkylated (for example with 2-chloroaceticacid). When using a different suitable ligand in the chiral osmylation,the enantiomers of C and then D and E can be produced. The hydroxylgroup in compound E can be mesylated and displaced with azide, andreduced to afford access to a wide variety of chiral3-aminosubsituted-1,2,3,4-tetrahydroquinolines. The opposite chiralityat the hydroxyl position is available using the analogous sequencereplacing with a suitable ligand for the chiral osmylation, may bemesylated and displaced with azide, which can be reduced to affordaccess to a wide variety of chiral3-aminosubsituted-1,2,3,4-tetrahydroquinolines.

Scheme 13 illustrates a general method of forming substituted(E)-7-(2-aryl-alken-1-en-1-yl)-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinolines, substituted(E)-6-(2-aryl-alken-1-en-1-yl)-4-(aryl orheteroarylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazines, andsubstituted (E)-N-alkyl-N-(3-(2-aryl-alken-1-en-1-yl)phenyl)(arene orheteroarene)sulfonamides. Copper(I)-catalyzed carboboration (see, forexample, R. Alfaro et al. in J. Am. Chem. Soc. 134: 15165-15168, 2012)of an aryl-alkyne affords tri- and tetrasubstitued vinylboronates thatare suitable for Pd-mediated stereoselective addition to the appropriate7-halo or 7-triflate-1,2,3,4-tetrahydroquinoline (A=CRR′), or 6-halo or6-triflate-3,4-dihydro-2H-benzo[b][1,4]oxazine (A=O) to afford the finalproduct.

Scheme 14 illustrates a general method of forming chiral substituted7-cyclopropyl-1-(aryl orheteroarylsulfonyl)-1,2,3,4-tetrahydroquinolines, 6-cyclopropyl-4-(arylor heteroarylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazines, orN-(3-cyclopropylphenyl)-N-alkyl(aryl or heteroaryl)sulfonamides C. Achiral cyclopropylboronic acid A (see, for example, M.-Z. Deng et al. inAngew. Chem. Ed. 37: 2845-2847, 1998) is added to the appropriatehaloarene or triflate B (X is halogen or triflate) to afford compound C.

Scheme 15 illustrates a general method for preparing various substitutedbenzoxazine compounds. Reaction of aryl sulfonamide A with an epoxideprovides benzoxazine B.

Scheme 16 illustrates another general method for preparing varioussubstituted benzoxazine compounds. Reaction of 2-fluoro-nitrobenzene Awith 2-hydroxyester B provides 2-O-arylacetic acid ester C. Reduction ofthe nitro moiety in C with a dissolving metal in an acid formssubstituted benzoxazinone D. The amide group in benzoxazinone D can bereduced using, for example, lithium aluminum hydride (LiAlH₄) or aborane to provide benzoxazine E, which is treated with a sulfonyl halideand base to afford sulfonylated benzoxazine F.

Scheme 17 illustrates a more specific example of a synthetic proceduregenerally illustrated in Scheme 16. Upon treatment with sodium nitritein aqueous hydrochloric acid, D-glutamic acid A is cyclized to thecarboxylic acid B. The carboxylic acid can be reduced to the alcoholwith borane, and then the resulting hydroxyl group is protected (e.g.,using a silyl or trityl moiety) to afford lactone C. Treatment of thelactone with LDA or LHDMS or another suitable base, followed byalkylation with an alkyl halide or alkyl triflate, affordsdiastereoselectively lactone D where Ry=H, and Rx is the alkyl moietyfrom the alkyl halide equivalent.

The other diastereomer of D where Ry and Rx are reversed can be preparedby treating lactone C with LDA and selectively protonating the enolatewith saturated sodium sulfate which acts effectively as a very hinderedproton source (see, for example, S. Takano et al. in Chem Lett 7331982). This enolate can also be alkylated selectively with a secondalkyl halide such that the product affords Rx as the second alkyl halidesource and Ry is from the first alkylation reaction.

Deprotection of the ether in compound D, followed by oxidation of theresulting hydroxyl group affords substituted carboxylic acid E.Treatment of E with acid in methanol affords substituted diester F,which when treated with a 2-nitrophenol affords substituted ester G.Cyclization which occurs during a dissolving metal reduction of Gaffords the substituted benzoxazinone H. The amide group inbenzoxazinone H can be selectively reduced using a borane to providebenzoxazine I, which is treated with a sulfonyl halide and base toafford the substituted sulfonylated benzoxazine J. If desired, the estergroup in J can be converted to a heterocycle using methods illustratedherein, such as in Schemes below.

Scheme 18 illustrates a general method for preparing various substitutedbenzoxazine compounds. Mitsunobu addition of sulfonamide A to chiralα-hydroxyester B affords O-aryl ether C. Treatment of compound C withDIBAL affords aldehyde D, to which vinyl magnesium bromide adds to formthe anti-aminoalcohol E (see, for example, D. Gryko et al. inTetrahedron: Asymmetry 8: 4059-4067, 1997). Treatment of compound E withbase affords benzoxazine F. The vinyl moiety in F may be converted toother alkenes via olefin metathesis chemistry, and the resulting alkenescan be reduced to substituted alkanes, or can be oxidized to a hydroxylgroup, a diol, a carboxylic acid, or other function group useful for theintroduction of a heterocyclic group.

Scheme 19 illustrates a general method for preparing chiral benzoxazineswith a heterocycle as a component of R^(2A). Literature reports by Linkand Corey demonstrate that trichloroketones can be reliablystereospecifically reduced with a proline-based catalyst and boranes andthen be displaced by phenols to afford substituted 2-phenoxycarboxylicacids (see, for example, Tetrahedron Lett 33: 3431-3434, 1992). Thereare a variety of methods to obtain trichloroketones (see for example,Tetrahedron Lett 33: 3435-3438, 1992), one of which is illustratedbelow. Treatment of an aldehyde A with trichloroacetic acid and sodiumtrichloroacetate in DMF affords racemic trichlorocarbinol B which can beoxidized with a chromate to afford trichloroketone C. Afterstereospecific reduction the chiral trichlorocarbinol D, in the presenceof hydroxide, a substituted 2-nitrophenol opens a 1,1-dichloroepoxideformed in the reaction conditions to afford substituted2-aryloxycarboxylic acid E. Esterification of E followed by a dissolvingmetal reduction affords substituted benzoxazinone G. The amide group inbenzoxazinone G can be reduced using, for example, lithium aluminumhydride (LiAlH₄) or a borane to provide benzoxazine H, which is treatedwith a sulfonyl halide and base to afford substituted sulfonylatedbenzoxazine I.

Scheme 20 illustrates a general method for preparing trisubstitutedolefins in a stereocontrolled manner. Aldehyde A (where A as O, A′=N)can be prepared based on procedures in Scheme 19, by utilizing asubstituted 4-hydroxy-3-nitrobenzaldehyde. Alternatively, aldehyde A canbe prepared by formylating a THQ or benzoxazine where X is Br or OTfwith Pd-mediated conditions; or by converting a bromide or triflate tothe nitrile and reducing the nitrile to the aldehyde with DIBAL. Thissubstituted aldehyde A can be reacted under Corey-Fuchs conditions (see,for example, Tetrahedron Lett 13: 3769-3772, 1972) with triphenylphosphine and carbon tetrabromide to form dibromo-olefin B. The bromidetrans- to the phenyl moiety of the benzoxazine or thetetrahydroquinoline can be selectively replaced with an aryl or alkylgroup (see, for example, Synlett 5 737-739, 2000; Tetrahedron 64:10250-1257; Angew Chem Int 51: 5718-5722; Org Lett 12: 2754-2757, 2010;and Org Lett 2797-3000, 2004) to form the bromo-substituted stilbene Cin a stereoselective manner. Addition of a second R via a secondPd-mediated catalyzed reaction affords a trisubstituted olefin D withgood stereocontrol.

Scheme 21 illustrates a general method for preparing trifluoromethylsubstituted olefin B in a stereocontrolled manner. It is a more specificexample of the general procedure illustrated in Scheme 20. Copper or Pd—mediated addition of a CF₃ to bromo-substituted stilbene A can introducethe substituent with retention of stereochemistry using conditionsdescribed in, for example, Adv Syn and Catalysis 353: 3044-3048, 2011.

Scheme 22 illustrates an alternative general method for preparingdisubstituted olefin D in a stereocontrolled manner. Copper-mediatedaddition of a bisboronate via the method of Hwanjong Jang et al. (see,for example, J. Am. Chem. Soc. 133: 7859-7871, 2011) to an acetylene Aaffords, in a stereospecific manner, vinyl boronate B. Palladiumcatalyzed coupling of the vinyl boronate to an aryl halide or aryltriflate C affords methyl-substituted olefin D.

Scheme 23 illustrates another general method for preparing disubstitutedolefins D in a stereocontrolled manner. Heck reaction of vinyl boronateA (see, for example, Andrew Lightfoot et al. in Tetrahedron Lett. 44:7645-7648, 2003) with an aryl halide or aryl triflate B affords vinylboronate C in a stereospecific manner. Palladium-catalyzed coupling ofthis boronate with an aryl or heteroaryl halide or triflate affordsdisubstituted olefin D.

Scheme 24 illustrates a general method for preparing substituted3-alkyoxy or 3-amino 1,2,4-oxadiazol-5(4H)-one D or1,2,4-trizol-5(4H)-one E. Treatment of alcohol A (Q=O) or an amine (Q=NHor N-lower alkyl) affords thiocarbamate B. The thiocarbamate may beconverted to 3-alkyoxy or 3-amino 1,2,4-oxadiazol-5(4H)-one D or1,2,4-trizol-5(4H)-one E by treatment with hydroxylamine or hydrazine inthe presence of a NaOH to facilitate the ring closure. Alternatively,sulfur may be alkyled and then the resulting compound reacted withhydroxylamine or hydrazine to obtain 3-alkyoxy or 3-amino1,2,4-oxadiazol-5(4H)-one D or 1,2,4-trizol-5(4H)-one E.

Scheme 25 illustrates a general method for preparing substituted1,3,4-oxadiazol-2(3H)-one C or 1,3,4-oxadiazole D. Treatment of ester Awith hydrazine affords hydrazide B that upon treatment with triphosgene(or a synthetic equivalent such as dicarbonyl imidazole) or an acidchloride affords, after cyclization, the substituted1,3,4-oxadiazol-2(3H)-one C or 1,3,4-oxadiazole D.

Scheme 26 illustrates a general method for preparing substituted1,2,4-oxadiazol-5(4H)-one C or 1,2,4-oxadiazole D. Treatment of nitrileA (Q=O) with hydroxylamine affords substituted N-hydroxyaceimidamide Bwhich upon treatment with triphosgene (or a synthetic equivalent such asdicarbonyl imidazole) or an acid chloride affords, after cyclization,substituted 1,2,4-oxadiazol-5(4H)-one C or 1,2,4-oxadiazole D.

Scheme 27 illustrates a general method for preparing substitutedN-linked heterocycle C. Treatment of alcohol A with methanesulfonylchloride or methane sulfonic anhydride affords mesylate B. Theintermediate B can also be a tosylate, triflate, halide, etc. Thisintermediate is displaced with a heterocycle having an NH group (e.g., asubstituted imidazole, pyrazole, triazole, etc) to afford N-linkedheterocycle C.

Scheme 28 illustrates an alternative general method for preparingsubstituted N-linked heterocycle B. Treatment of alcohol A withMitsunobu conditions (e.g., triphenyl phosphine or its equivalent withdiisopropyldiazodicarboxylate or its equivalent) with an acidicNH-substituted heterocycle (e.g., a substituted pyrrolidin-2,5-dione,1-alkylimidazolin-2,4-dione, imidazoline-2,4-dione,oxazolidin-2,4-dione, or thiazolidine-2,4-dione) affords N-linkedheterocycle B.

Scheme 29 illustrates a general method for preparing substitutedC-linked heterocycle C. Treatment of alcohol A with methanesulfonylchloride or methane sulfonic anhydride affords mesylate B. Theintermediate B can also be a tosylate, triflate, halide, etc. Thisintermediate may be displaced by a carbanion of a variety ofC-heterocycles (e.g., a substituted pyrrolidin-2-one, piperidin-2-one,thiazolidine-2,4-dione, imidazolidine-2,4-dione, oroxazolidin-2,4-dione) to afford C-linked heterocycle C.

Scheme 30 illustrates a general method for preparing substituted(2S,4R)-2-substituted-4-(aryl or heteroaryl sulfonyl)chroman F.Treatment of benzylic halide A with mercaptan B affords thioether C.Oxidation of thioether C with meta-chloroperbenzoic acid or anotheroxidant affords sulfone D. Treatment of sulfone D with n-butyl lithium,tert-butoxide or another suitable base forms an anion which can bealkylated with an epoxide to afford alcohol E. Treatment of alcohol Ewith sodium hydride or another suitable base affords the chroman F.

Scheme 31 illustrates another general method of forming substituted(benzyl or heteroarylalkyl sulfonyl)benzene E. Condensation of2-hydroxyacetophenone A with aldehyde B catalyzed by pryrrolidineaffords chromanone C. Addition of a thiol to chromanone C under acidicconditions (e.g., BF₃-etherate or trifluoroacetic acid) in the presenceof a reductant (e.g., triethylsilane or pyridine borane) affords sulfideD. Oxidation of sulfide D with metachloroperbenzoic acid, oxone, orother suitable oxidant affords substituted (benzyl or heteroarylalkylsulfonyl)benzene E.

Scheme 32 illustrates a general method for forming substituted 1-(phenylor heteroarylsulfonyl)-1,2,3,4-tetrahydronaphthalene C. Addition of athiol under acidic conditions (e.g., BF₃-etherate or trifluoroaceticacid) in the presence of a reductant (triethylsilane or pyridine borane)to etralone A affords sulfide B. Oxidation of sulfide B withmetachloroperbenzoic acid, oxone, or other suitable oxidant affords1-(phenyl or heteroarylsulfonyl)-1,2,3,4-tetrahydronaphthalene C.

II. Therapeutic Applications of Dihydro-2H-benzo[b][1,4]oxazineSulfonamide and Related Compounds

It is contemplated that the dihydro-2H-benzo[b][1,4]oxazine sulfonamideand related compounds described herein, such as a compound of Formula I,I-A, I-B, II, II-A, II-B, II-C, or other compounds in Section I, providetherapeutic benefits to subjects suffering from a cancer, bacterialinfection, fungal infection, or immune deficiency disorder. Accordingly,one aspect of the invention provides a method of treating a disorderselected from the group consisting of cancer, bacterial infection,fungal infection, and immune deficiency disorder. The method comprisesadministering a therapeutically effective amount of adihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compounddescribed herein, such as a compound of Formula I, I-A, I-B, II, II-A,II-B, II-C, or other compounds in Section I, to a subject in needthereof to ameliorate a symptom of the disorder. In certain embodiments,the particular compound of Formula I, I-A, I-B, II, II-A, II-B, or II-Cis a compound defined by one of the embodiments described above.

In certain embodiments, the disorder is cancer. In certain embodiments,the cancer is a solid tumor or leukemia. In certain other embodiments,the cancer is colon cancer, pancreatic cancer, breast cancer, ovariancancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lungcancer, leukemia, bladder cancer, stomach cancer, cervical cancer,testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidneycancer, uterus cancer, espophagus cancer, liver cancer, an acousticneuroma, oligodendroglioma, meningioma, neuroblastoma, orretinoblastoma. In certain other embodiments, the cancer is small celllung cancer, non-small cell lung cancer, melanoma, cancer of the centralnervous system tissue, brain cancer, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, ordiffuse large B-Cell lymphoma. In certain other embodiments, the canceris breast cancer, colon cancer, small-cell lung cancer, non-small celllung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia,melanoma, or cancer of the central nervous system tissue. In certainother embodiments, the cancer is colon cancer, small-cell lung cancer,non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer,or melanoma.

Additional exemplary cancers include fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelialcarcinoma, glioma, astrocytoma, medulloblastoma, and hemangioblastoma.

In certain embodiments, the cancer is a neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectalcancer, unresectable colorectal carcinoma, metastatic hepatocellularcarcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low gradefollicular lymphoma, metastatic melanoma, localized melanoma, malignantmesothelioma, malignant pleural effusion mesothelioma syndrome,peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma,soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cellhistiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive,hormone refractory prostate cancer, resected high-risk soft tissuesarcoma, unrescectable hepatocellular carcinoma, Waidenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen independent prostate cancer, androgen dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

In certain embodiments, the disorder is a bacterial infection. Thebacterial infection can be characterized according to classificationsknown in the art. For example, in certain embodiments, the bacterialinfection is a gram-positive bacterial infection, such as agram-positive cocci bacterial infection or a gram-positive bacillibacterial infection. In other embodiments, the bacterial infection is agram-negative bacterial infection, such as a gram-negative coccibacterial infection or a gram-negative bacilli bacterial infection. Thebacterial infection can also be characterized according to whether it iscaused by anaerobic or aerobic bacteria. Accordingly, in certainembodiments, the bacterial infection is an anaerobic bacterialinfection. In certain other embodiments, the bacterial infection is anaerobic bacterial infection.

A variety of bacteria are contemplated to be susceptible to thetetrahydroquinoline compounds. Representative bacteria includeStaphylococci species, e.g., S. aureus; Enterococci species, e.g., E.faecalis and E. faecium; Streptococci species, e.g., S. pyogenes and S.pneumoniae; Escherichia species, e.g., E. coli, includingenterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic andenteroaggregative E. coli strains; Haemophilus species, e.g., H.influenza; and Moraxella species, e.g., M. catarrhalis. Other examplesinclude Mycobacteria species, e.g., M. tuberculosis, M.avian-intracellulare, M. kansasii, M. bovis, M. africanum, M. genavense,M. leprae, M. xenopi, M. simiae, M. scrofulaceum, M. malmoense, M.celatum, M. abscessus, M. chelonae, M. szulgai, M. gordonae, M.haemophilum, M. fortuni and M. marinum; Corynebacteria species, e.g., C.diphtheriae; Vibrio species, e.g., V. cholerae; Campylobacter species,e.g., C. jejuni; Helicobacter species, e.g., H. pylori; Pseudomonasspecies, e.g., P. aeruginosa; Legionella species, e.g., L. pneumophila;Treponema species, e.g., T. pallidum; Borrelia species, e.g., B.burgdorferi; Listeria species, e.g., L. monocytogenes; Bacillus species,e.g., B. cereus; Bordatella species, e.g., B. pertussis; Clostridiumspecies, e.g., C. perfringens, C. tetani, C. difficile and C. botulinum;Neisseria species, e.g., N. meningitidis and N. gonorrhoeae; Chlamydiaspecies, e.g., C. psittaci, C. pneumoniae and C. trachomatis; Rickettsiaspecies, e.g., R. rickettsii and R. prowazekii; Shigella species, e.g.,S. sonnei; Salmonella species, e.g., S. typhimurium; Yersinia species,e.g., Y. enterocolitica and Y. pseudotuberculosis; Klebsiella species,e.g., K. pneumoniae; Mycoplasma species, e.g., M. pneumoniae; andTrypanosoma brucei. In certain embodiments, the compounds describedherein are used to treat a subject suffering from a bacterial infectionselected from the group consisting of S. aureus, E. faecalis, E.faecium, S. pyogenes, S. pneumonia, and P. aeruginosa.

The antibacterial activity of compounds described herein may beevaluated using assays known in the art, such as the microbroth dilutionminimum inhibition concentration (MIC) assay, as further described inNational Committee for Clinical Laboratory Standards. PerformanceStandards for Antimicrobial Susceptibility Testing; FourteenthInformational Supplement. NCCLS document M100-S14 {ISBN 1-56238-516-X}.This assay may be used to determine the minimum concentration of acompound necessary to prevent visible bacterial growth in a solution. Ingeneral, the drug to be tested is serially diluted into wells, andaliquots of liquid bacterial culture are added. This mixture isincubated under appropriate conditions, and then tested for growth ofthe bacteria. Compounds with low or no antibiotic activity (a high MIC)will allow growth at high concentrations of compound, while compoundswith high antibiotic activity will allow bacterial growth only at lowerconcentrations (a low MIC).

The assay uses stock bacterial culture conditions appropriate for thechosen strain of bacteria. Stock cultures from the permanent stockculture collection can be stored as frozen suspensions at −70° C.Cultures may be suspended in 10% skim milk (BD) prior to snap freezingin dry ice/ethanol and then placed in a −70° C. freezer. Cultures may bemaintained on Tryptic Soy Agar containing 5% Sheep Blood at roomtemperature (20° C.), and each culture may be recovered from frozen formand transferred an additional time before MIC testing. Fresh plates areinoculated the day before testing, incubated overnight, and checked toconfirm purity and identity.

The identity and purity of the cultures recovered from the stock culturecan be confirmed to rule out the possibility of contamination. Theidentity of the strains may be confirmed by standard microbiologicalmethods (See, e.g., Murray et al., Manual of Clinical Microbiology,Eighth Edition. ASM Press {ISBN 1-55581-255-4}). In general, culturesare streaked onto appropriate agar plates for visualization of purity,expected colony morphology, and hemolytic patterns. Gram stains can alsobe utilized. The identities are confirmed using a MicroScan WalkAway 40SI Instrument (Dade Behring, West Sacramento, Calif.). This deviceutilizes an automated incubator, reader, and computer to assess foridentification purposes the biochemical reactions carried out by eachorganism. The MicroScan WalkAway can also be used to determine apreliminary MIC, which may be confirmed using the method describedbelow.

Frozen stock cultures may be used as the initial source of organisms forperforming microbroth dilution minimum inhibition concentration (MIC)testing. Stock cultures are passed on their standard growth medium forat least 1 growth cycle (18-24 hours) prior to their use. Most bacteriamay be prepared directly from agar plates in 10 mL aliquots of theappropriate broth medium. Bacterial cultures are adjusted to the opacityof a 0.5 McFarland Standard (optical density value of 0.28-0.33 on aPerkin-Elmer Lambda EZ150 Spectrophotometer, Wellesley, Mass., set at awavelength of 600 nm). The adjusted cultures are then diluted 400 fold(0.25 mL inoculum+100 mL broth) in growth media to produce a startingsuspension of approximately 5×105 colony forming units (CFU)/mL. Mostbacterial strains may be tested in cation adjusted Mueller Hinton Broth(CAMHB).

Test compounds (“drugs”) are solubilized in a solvent suitable for theassay, such as DMSO. Drug stock solutions may be prepared on the day oftesting. Microbroth dilution stock plates may be prepared in twodilution series, 64 to 0.06 μg drug/mL and 0.25 to 0.00025 μg drug/mL.For the high concentration series, 200 μL of stock solution (2 mg/mL) isadded to duplicate rows of a 96-well microtiter plate. This is used asthe first well in the dilution series. Serial two-fold decrementaldilutions are made using a BioMek FX robot (Beckman Coulter Inc.,Fullerton, Calif.) with 10 of the remaining 11 wells, each of which willcontain 100 μL of the appropriate solvent/diluent. Row 12 containssolvent/diluent only and serves as the control. For the first well ofthe low concentration series, 200 μL of an 8 μg/mL stock are added toduplicate rows of a 96-well plate. Serial two-fold dilutions are made asdescribed above.

Daughter 96-well plates may be spotted (3.2 μL/well) from the stockplates listed above using the BioMek FX robot and used immediately orfrozen at −70° C. until use. Aerobic organisms are inoculated (100 μLvolumes) into the thawed plates using the BioMek FX robot. Theinoculated plates are be placed in stacks and covered with an emptyplate. These plates are then incubated for 16 to 24 hours in ambientatmosphere according to CLSI guidelines (National Committee for ClinicalLaboratory Standards, Methods for Dilution, Antimicrobial Tests forBacteria that Grow Aerobically; Approved Standard-Sixth Edition. NCCLSdocument M7-A6 {ISBN 1-56238-486-4}).

After inoculation and incubation, the degree of bacterial growth can beestimated visually with the aid of a Test Reading Mirror (DynexTechnologies 220 16) in a darkened room with a single light shiningdirectly through the top of the microbroth tray. The MIC is the lowestconcentration of drug that prevents macroscopically visible growth underthe conditions of the test.

In certain embodiments, the disorder is a fungal infection. Exemplaryfungi that may be treated include, for example, Acremonium, Absidia(e.g., Absidia corymbifera), Alternaria, Aspergillus (e.g., Aspergillusclavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillusnidulans, Aspergillus niger, Aspergillus terreus, and Aspergillusversicolor), Aureobasidium, Basidiobolus, Blastomyces (e.g., Blastomycesdermatitidis), Candida (e.g., Candida albicans, Candida glabrata,Candida guilliermondii, Candida kefyr, Candida krusei, Candidalusitaniae, Candida parapsilosis, Candida pseudotropicalis, Candidastellatoidea, Candida tropicalis, Candida utilis, Candida lipolytica,Candidafamata and Candida rugosa), Cephalosporium, Chaetomium,Chrysosporium, Cladosporium (e.g., Cladosporium carrionii andCladosporium trichloides), Coccidioides (e.g., Coccidioides immitis),Conidiobolus, Coprinus, Corynespora, Cryptococcus (e.g., Cryptococcusneoformans), Curvularia, Cunninghamella (e.g., Cunninghamella elegans),Exophiala (e.g., Exophiala dermatitidis and Exophiala spinifera),Epidermophyton (e.g., Epidermophyton floccosum), Fonsecaea (e.g.,Fonsecaea pedrosoi), Fusarium (e.g., Fusarium solani), Geotrichum (e.g.,Geotrichum candiddum and Geotrichum clavatum), Hendersonula,Histoplasma, Leptosphaeria, Loboa, Madurella, Malassezia (e.g.,Malassezia furfur), Microsporum (e.g., Microsporum canis and Microsporumgypseum), Mycocentrospora, Mucor, Neotestudina, Paecilomyces,Paracoccidioides (e.g., Paracoccidioides brasiliensis), Penicillium(e.g., Penicillium marneffei), Phialophora, Pneumocystis (e.g.,Pneumocystis carinii), Pseudallescheria (e.g., Pseudallescheria boydii),Rhinosporidium, Rhizomucor, Rhizopus (e.g., Rhizopus microsporus var.rhizopodiformis and Rhizopus oryzae), Saccharomyces (e.g., Saccharomycescerevisiae), Scopulariopsis, Sporothrix (e.g., Sporothrix schenckii),Trichophyton (e.g., Trichophyton mentagrophytes and Trichophytonrubrum), Trichosporon (e.g., Trichosporon asahii, Trichosporon beigeliiand Trichosporon cutaneum), and Wangiella.

In certain embodiments, the disorder is an immune deficiency disorder.Exemplary immune deficiency disorders include, for example, a humanimmunodeficiency viral infection, a patient with a deficient immunesystem due to chemotherapy, or a patient recovering from surgery who hasa deficient immune system.

In certain embodiments, the subject is a human.

Another aspect of the invention provides for the use of a compounddescribed herein (such as a compound of Formula I, I-A, I-B, II, II-A,II-B, II-C, or other compounds in Section I) in the manufacture of amedicament. In certain embodiments, the medicament is for treating adisorder described herein, such as cancer.

Another aspect of the invention provides for the use of a compounddescribed herein (such as a compound of Formula I, I-A, I-B, II, II-A,II-B, II-C, or other compounds in Section I) for treating a medicaldisorder, such a medical disorder described herein (e.g., cancer).

Further, it is contemplated that dihydro-2H-benzo[b][1,4]oxazinesulfonamide and related compounds described herein, such as a compoundof Formula I, I-A, I-B, II, II-A, II-B, II-C, or other compounds inSection I, can promote the activity of RORγ. Accordingly, another aspectof the invention provides a method of promoting the activity of RORγ.The method comprises exposing a RORγ to an effective amount of adihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compounddescribed herein, such as a compound of Formula I, I-A, I-B, II, II-A,II-B, II-C, or other compounds in Section I, to promote RORγ activity.In certain embodiments, the particular compound of Formula I, I-A, I-B,II, II-A, II-B, or II-C is the compound defined by one of theembodiments described above. Promoting the activity of RORγ means toincrease the activity of RORγ. In certain embodiments, exposing a RORγto an effective amount of a dihydro-2H-benzo[b][1,4]oxazine sulfonamideor related compound described herein (such as a compound of Formula I,I-A, I-B, II, II-A, II-B, II-C, or other compounds in Section I) resultsin an increase in RORγ activity of at least 5%, 10%, 20%, or 50%relative to the activity of RORγ under substantially the same conditionsbut without the presence of the dihydro-2H-benzo[b][1,4]oxazinesulfonamide or related compound.

Further, it is contemplated that dihydro-2H-benzo[b][1,4]oxazinesulfonamide and related compounds described herein, such as a compoundof Formula I, I-A, I-B, II, II-A, II-B, II-C, or other compounds inSection I, can increase the amount of interleukin-17 (IL-17) in asubject. IL-17 is a cytokine that affects numerous biological functions.Accordingly, another aspect of the invention provides a method ofincreasing the amount of IL-17 in a subject. The method comprisesadministering to a subject an effective amount of adihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compounddescribed herein, such as a compound of Formula I, I-A, I-B, II, II-A,II-B, II-C, or other compounds in Section I, to increase the amount ofIL-17 in the subject. In certain embodiments, the particular compound ofFormula I, I-A, I-B, II, II-A, II-B, or II-C is the compound defined byone of the embodiments described above.

In certain embodiments, the subject is a human. In certain embodiments,administering the compound increases the amount of IL-17 produced byTh-17 cells in the subject. A change in the amount of IL-17 produced by,for example, Th-17 cells can be measured using procedures described inthe literature, such as an ELISA assay or intracellular staining assay.

Further, it is contemplated that dihydro-2H-benzo[b][1,4]oxazinesulfonamide and related compounds described herein, such as a compoundof Formula I, I-A, I-B, II, II-A, II-B, II-C, or other compounds inSection I, may increase the synthesis of IL-17 in a subject.Accordingly, another aspect of the invention provides a method ofincreasing the synthesis of IL-17 in a subject. The method comprisesadministering to a subject an effective amount of a compound describedherein, e.g., a compound of Formula I, I-A, I-B, II, II-A, II-B, II-C orother compounds in Section I, to increase the synthesis of IL-17 in thesubject. In certain embodiments, the particular compound of Formula I,I-A, I-B, II, II-A, II-B, or II-C is a compound defined by one of theembodiments described above.

Adoptive Cellular Therapy

RORγ agonist compounds described herein may also be used in adoptivecellular therapy to treat various medical disorders, such as cancer,bacterial infections, fungal infections, and immune disorders. Cells,e.g., lymphocyte cells or dendritic cells, are exposed ex vivo to anRORγ agonist compound herein, and then the treated cells areadministered to a patient. In adoptive cellular transfer, cells areobtained from a source (typically the patient in need of treatment),cultured ex vivo with an agent, and then the resulting cells areadministered to the patient in need of therapy. The culturing typicallysubjects the cells to conditions whereby the cells increase in number(i.e., expansion) and/or acquire features providing improved therapeuticbenefit. General features of the adoptive cellular therapy methods andcompositions are described below, along with more specific embodimentsof the lymphocyte cells, dendritic cells, and procedures for isolatingand culturing cells.

Accordingly, one aspect of the invention provides a method of deliveringto a patient a RORγ agonist treated cell selected from the groupconsisting of a lymphocyte cell and dendritic cell. The method comprisesadministering to a patient in need thereof a pharmaceutical compositioncomprising said cell that has been exposed ex vivo to an agonist of RORγdescribed herein, such as a compound of Formula I, I-A, I-B, II, II-A,II-B, or II-C. The method may further comprise a culturing step. In suchembodiments, the method further comprises culturing a cell (i.e., thelymphocyte cell or dendritic cell) with an agonist of RORγ to providethe cell that has been exposed ex vivo to the agonist of RORγ. Theculturing may comprise exposing the cell to a cytokine (e.g., IL-13,IL-2, IL-6, IL-7, IL-10, IL-12, IL-15, IL-18, IL-21, IL-23, ortransforming growth factor beta). During the culturing step, the cellmay be exposed to an antigen associated with a medical disorder.Although not to be bound by theory, cells having an receptor specific toan antigen associated with a medical disorder can provide a moreeffective therapy than cells lacking such a receptor. Accordingly, incertain embodiments, the culturing step comprises exposing the cell toan antigen associated with a medical disorder. The antigen may be anantigen presenting cell. Alternatively, the antigen may comprise cancertissue. Further, as described below, the cell may be genetically alteredto express a receptor specific to an antigen associated with a medicaldisorder.

The cell may be autologous or allogenic. Autologous cells are cellsobtained from the patient whom will receive the cell exposed ex vivo toan agonist of RORγ. As such, in certain embodiments, the method mayfurther comprise obtaining a cell from said patient, for use in theculturing step. Alternatively, the cells may be allogenic, i.e.,obtained from a subject that produces cells allogenic to cells of thepatient. In such embodiments, the method may further comprise obtaininga cell from a subject that produces cells allogenic to lymphocyte cellsof the patient, for use in the culturing step.

In certain embodiments, the cell is a lymphocyte cell. Lymphocyte cellscan be obtained from human or animal tissues according to proceduresdescribed in the literature. In certain embodiments, the lymphocyte cellis obtained from blood, cancer tissue, bone marrow, the spleen, a lymphnode, or the thymus. In certain other embodiments, the lymphocyte cellis obtained from a population of peripheral blood mononuclear cells,such as human peripheral blood mononuclear cells. In certain otherembodiments, the lymphocyte cell is obtained from a lymph node inproximity to a tumor or site of infection. In certain other embodiments,the lymphocyte cell is obtained from cancer tissue. In yet otherembodiments, the lymphocyte cell is a tumor-infiltrating-lymphocytecell.

Cells can be characterized according to the presence of a receptor foran antigen specific for a medical disorder. In certain embodiments, thecell expresses a receptor for an antigen specific for a medicaldisorder. As indicate above, such cells may provide more effectivetherapies for treating disease since the cells are more likely to targettissue specific to the disease to be treated. In certain embodiments,the medical disorder is a cancer, bacterial infection, fungal infection,or immune disorder. In yet other embodiments, the cell may express areceptor that, while not specific for a medical disorder, has utility inenhancing cell efficacy in treating the disorder.

Various types of lymphocyte cells have been described in the literaturefor use in adoptive cellular transfer. In certain embodiments, thelymphocyte cell is a T cell. In certain other embodiments, thelymphocyte cell is a CD8⁺ T cell, CD4⁺ T cell, or T_(H)17 cell. Incertain other embodiments, the lymphocyte cell is a CD8⁺ T cell, CD4⁺ Tcell, or a combination thereof. In certain other embodiments, thelymphocyte cell is a natural killer cell. In certain other embodiments,the lymphocyte cell is a Tc17 cell, natural killer T cell, or γδ T cell.In yet other embodiments, the lymphocyte cell is a genetically alteredlymphocyte cell.

Cells may be administered to the patient according to proceduresdescribed in the literature. In certain embodiments, the administeringcomprises injecting into the patient the pharmaceutical composition. Theinjecting may be intravenous injection or injection directly intodiseased tissue, such as a tumor. In yet other embodiments, theinjecting may be subcutaneous injection into the patient.

The therapeutic method embraces combination therapies, such asadministering (i) an agent that enhances the efficacy of the cellexposed to the agonist of RORγ and/or (ii) an agent having independentefficacy in treating the target medical disorder.

Another aspect of the invention provides a method of preparing apopulation of cells that have been exposed ex vivo to an agonist of RORγdescribed herein, where the cells are lymphocyte cells and/or dendriticcells. The method comprises exposing a population of cells selected fromthe group consisting of lymphocyte cells and dendritic cells ex vivo toan agonist of RORγ described herein to thereby provide said populationof cells that have been exposed ex vivo to an agonist of RORγ. Thepopulation of cells may be used in therapeutic methods described herein.The exposing step may comprise culturing a population of cells with theagonist of RORγ for a duration of time sufficient to increase the numberof cells in the population. The culturing may comprise exposing the cellto a cytokine (e.g., IL-13, IL-2, IL-6, IL-7, IL-10, IL-12, IL-15,IL-18, IL-21, IL-23, or transforming growth factor beta). Further duringthe culturing step, the cell may optionally be exposed to an antigenassociated with a medical disorder. Accordingly, in certain embodiments,the culturing step comprises exposing the cell to an antigen associatedwith a medical disorder. The antigen may be an antigen presenting cell.Alternatively, the antigen may comprise cancer tissue. The cell may beautologous or allogenic. Autologous cells are cells obtained from thepatient whom will receive the cell exposed ex vivo to an agonist ofRORγ. As such, in certain embodiments, the method may further compriseobtaining a cell (i.e., a lymphocyte or dendritic cell) from saidpatient for use in the culturing step. Alternatively, the cells may beallogenic, i.e., obtained from subject that produces cells allogenic tocells of the patient. In such embodiments, the method may furthercomprise obtaining a cell from a subject that produces cells allogenicto cells of the patient, for use in the culturing step. In certainembodiments, the cell is a lymphocyte cell. Lymphocyte cells can beobtained from human or animal tissues according to procedures describedin the literature. In certain embodiments, the lymphocyte cell isobtained from blood, cancer tissue, bone marrow, the spleen, a lymphnode, or the thymus. In certain other embodiments, the lymphocyte cellis obtained from a population of peripheral blood mononuclear cells,such as human peripheral blood mononuclear cells. In certain otherembodiments, the lymphocyte cell is obtained from a lymph node inproximity to a tumor or site of infection. In certain other embodiments,the lymphocyte cell is obtained from cancer tissue. In yet otherembodiments, the lymphocyte cell is a tumor-infiltrating-lymphocytecell.

Cells can be characterized according to the presence of a receptor foran antigen specific for a medical disorder. In certain embodiments, thecell expresses a receptor for an antigen specific for a medicaldisorder. As indicated above, such cells may provide more effectivetherapies for treating disease since the cells is more likely to targettissue specific to the disease to be treated. In certain embodiments,the medical disorder is a cancer, bacterial infection, fungal infection,or immune disorder. In yet other embodiments, the cell may express areceptor that, while not specific for a medical disorder, has utility inenhancing cell efficacy in treating the disorder.

As described above, various types of lymphocyte cells have beendescribed in the literature for use in adoptive cellular transfer. Incertain embodiments, the lymphocyte cell is a T cell. In certain otherembodiments, the lymphocyte cell is a CD8⁺ T cell, CD4⁺ T cell, orT_(H)17 cell. In certain other embodiments, the lymphocyte cell is aCD8⁺ T cell, CD4⁺ T cell, or a combination thereof. In certain otherembodiments, the lymphocyte cell is a natural killer cell. In certainother embodiments, the lymphocyte cell is a Tc17, natural killer T cell,or γδ T cell. In yet other embodiments, the lymphocyte cell is agenetically altered lymphocyte cell.

Another aspect of the invention provides a method of treating a medicaldisorder. The method comprises administering to a patient in needthereof a cell that has been exposed ex vivo to an agonist of RORγdescribed herein to treat the medical disorder, wherein the cell is alymphocyte cell or dendritic cell. The medical disorder can be, forexample, a cancer, bacterial infection, fungal infection, or immunedisorder. Additional exemplary medical disorders are described above,and in certain embodiments, the medical disorder is a cancer selectedfrom the group consisting of a solid tumor, lymphoma, and leukemia. Incertain other embodiments, the medical disorder is a cancer selectedfrom the group consisting of ovarian cancer, melanoma, colorectalcancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer,renal cell carcinoma, leukemia, a B-cell lymphoma, and non-Hodgkinlymphoma.

Another aspect of the invention provides a population of lymphocytecells that have been exposed ex vivo to an agonist of RORγ describedherein. The population may be characterized by the presence and/orquantity of particular types of cells in the population. For example, incertain embodiments, the population comprises one or more of thefollowing: T cells and natural killer cells. In certain otherembodiments, a majority of lymphocyte cells in the population are Tcells. In certain other embodiments, a majority of lymphocyte cells inthe population are CD8⁺ T cells, CD4⁺ T cells, T_(H)17 cells, or acombination thereof. In yet other embodiments, a majority of lymphocytecells in the population are natural killer cells. In yet otherembodiments, a single type of lymphocyte cell (e.g., a T cell, CD8⁺ Tcell, CD4⁺ T cell, T_(H)17 cell, Tc17 cell, natural killer T cell, or γδT cell) comprises at least 60%, 70% 80%, 90% or 95% of the cells in thepopulation. In yet other embodiments, the population is characterizedby: (i) a majority of lymphocyte cells in the population are T cells,(ii) a majority of lymphocyte cells in the population are CD8⁺ T cells,CD4⁺ T cells, T_(H)17 cells, or a combination thereof, (iii) a majorityof lymphocyte cells in the population are Tc17 cells, (iv) a majority oflymphocyte cells in the population are natural killer cells, or (v) amajority of lymphocyte cells in the population are natural killer Tcells, γδ T cells, or a combination thereof. In yet other embodiments, amajority of lymphocyte cells in the population are CD8⁺ T cells, CD4⁺ Tcells, or a combination thereof. In yet other embodiments, thepopulation is characterized by a majority of lymphocyte cells in thepopulation are Tc17 cells, CD4⁺ Th0 T lymphocyte cells, Th17-polarizedCD4+T lymphocyte cells, CD8+Tc17 T lymphocyte cells, or a combinationthereof.

In each of the above aspects and embodiments, lymphocyte cells may becharacterized according to whether they are a tumor infiltratinglymphocyte, naïve T lymphocyte, memory T lymphocyte, effector Tlymphocyte, CD8⁺ T cell, CD4⁺ T cell, CD4⁺/CD8⁺ double positive Tlymphocyte, CD28⁺CD8⁺ T cell, or T_(H)17 cell. CD8⁺ T cells can beseparated into naïve CD8⁺ T cells, memory CD8⁺ T cells, and effectorCD8⁺ T cells, according to cell surface antigens characteristic to eachtype of cell. Whether a cell or cell population is positive for aparticular cell surface marker can be determined by flow cytometry usingstaining with a specific antibody for the surface marker and an isotypematched control antibody. A cell population negative for a marker refersto the absence of significant staining of the cell population with thespecific antibody above the isotype control, and positive refers touniform staining of the cell population above the isotype control. Forinstance, CD4⁺ T helper cells can be sorted into naïve, central memory,and effector cells by identifying cell populations that have cellsurface antigens. In certain embodiments, central memory CD4⁺ T cellsare CD62L positive and CD45RO positive. In certain embodiments, effectorCD4⁺ T cells are CD62L and CD45RO negative. In yet other embodiments,the lymphocyte cell is a Th1 cell, Tc1 cell, Th0 cell, or Tc0 cell. Incertain embodiments, the lymphocyte cell is a CD8⁺ T cell, which isoptionally further characterized according to the whether the CD8⁺ Tcell is a naïve CD8⁺ T cell, a memory CD8⁺ T cell, or an effector CD8⁺ Tcell. In certain embodiments, the lymphocyte cell is a memory CD8⁺ Tcell, which may be further characterized according to whether the cellis CD62L positive or CD45RO positive. In certain other embodiments, thelymphocyte cell is an effector CD8⁺ T cell, which may be furthercharacterized according to whether the cell is CD62L negative or CD45ROnegative. In yet other embodiments, the lymphocyte cell is a CD4+Th0 Tlymphocyte, Th17-polarized CD4+T lymphocyte, or CD8+Tc17 T lymphocyte.In still other embodiments, the lymphocyte cell is a memory T cellpresent in CD62L+ or CD62L− subsets of CD8+ peripheral bloodlymphocytes. In certain embodiments, the central memory T cells may beCD45RO+, CD62L+, CD8+ T cells. In certain embodiments, effector T cellsare negative for CD62L, CCR7, CD28, and CD127, and positive for granzymeB and perforin.

T cells can be characterized according to identity of a T cell receptorlocated on the surface of the T cell. The T cell receptor is adisulfide-linked membrane-anchored heterodimer that normally consists ofhighly variable alpha (c) and beta (3) chains expressed as part of acomplex with the invariant CD3 chain molecules. T cells expressing thisreceptor are referred to as α:β (or αβ) T cells. A minority of T cellsexpress an alternate receptor, formed by variable gamma (γ) and delta(δ) chains, and such T cells are referred as γδ T cells. One subtype ofT cells is natural killer T (NKT) cells. NKT cells are a heterogeneousgroup of T cells that share properties of both T cells and naturalkiller NK cells. Many NKT cells recognize the non-polymorphic CD1dmolecule, an antigen-presenting molecule that binds self- and foreignlipids and glycolipids. Other subtypes of T cells include, for example,CD8⁺ T cells, CD4⁺ T cells, Tc17 cells, natural killer T cells, and γδ Tcells. Still other subtypes of T cells include, for example, CD4⁻CD8⁻ Tcells and CD28⁺CD8⁺ T cells.

Preferably the lymphocyte cell comprises a receptor specific for anantigen of a medical condition. The receptor can be the endogenouslymphocyte cell receptor, i.e., the antigen-specific lymphocyte cellreceptor that is endogenous (i.e., native to) the lymphocyte. In suchinstances, the lymphocyte comprising the endogenous lymphocyte cellreceptor can be a lymphocyte cell that was isolated from the patient,which is known to express the particular medical condition-specificantigen. Alternatively, the lymphocyte comprising the endogenouslymphocyte cell receptor can be a lymphocyte cell that was isolated froma subject that produces allogenic lymphocyte cells (i.e., lymphocytecells that are histocompatible with the patient that will receive thelymphocyte cells). In certain embodiments, the subject from whichlymphocyte cells are obtained may be immunized prior to obtaining thelymphocyte cells, so that the lymphocyte cells to be administered to thepatient will have specificity for the medical disorder to be treated.

The antigen of a disease recognized by the endogenous lymphocyte cellreceptor can be any antigen which is characteristic of the disease. Forexample, the antigen may be, for example, a tumor antigen, such asgp100, MART-1, TRP-1, TRP-2, tyrosinase, NY-ESO-1, MAGE-1, or MAGE-3.

Lymphocyte cells may also be characterized according to the presence ofa phenotypic marker of activation for tumor reactivity, such as thepresence of 4-1BBL. Populations of lymphocyte cells enriched for such aphenotypic marker may provide therapeutic advantages. Lymphocyte cellsmay also be characterized according to the level of expression of theRORγ. In certain embodiments, the lymphocyte cell may be induced toexpress or engineered to express RORγ, thereby increasing the amount ofRORγ.

The lymphocyte cell may be a genetically modified lymphocyte cell, suchas a genetically modified lymphocyte cell described in, for example,International Patent Application Publication No. WO 2012/129514, whichis hereby incorporated by reference. Genetic modification of thelymphocyte may improve the efficacy of therapy by promoting theviability and/or function of transferred lymphocyte cells, provide agenetic marker to permit selection and/or evaluation of in vivo survivalor migration, or may incorporate functions that improve the safety ofimmunotherapy, for example, by making the cell susceptible to negativeselection in vivo. The lymphocyte may be genetically modified so thatthe lymphocyte cell expresses certain proteins, such as a survivalcytokine (e.g., granulocyte-macrophage colony-stimulating factor) and/orreceptor for an antigen (e.g., a tumor antigen).

Accordingly, in embodiments, lymphocyte cells are modified with chimericantigen receptors (CAR). The CARs may comprise a single-chain antibodyfragment (scFv) that is derived from the variable heavy (VH) andvariable light (VL) chains of a monoclonal antibody (mAb) linked to theTCR CD3⁺ chain that mediates T-cell activation and cytotoxicity.Costimulatory signals can also be provided through the CAR by fusing thecostimulatory domain of CD28 or 4-1 BB to the CD3⁺ chain. CARs arespecific for cell surface molecules independent from HLA, thusovercoming the limitations of TCR-recognition including HLA-restrictionand low levels of HLA-expression on tumor cells.

III. Combination Therapy

Another aspect of the invention provides for combination therapy.Dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds (e.g.,a compound of Formula I, I-A, I-B, II, II-A, II-B, II-C, or othercompounds in Section I) or their pharmaceutically acceptable salts maybe used in combination with additional therapeutic agents to treatmedical disorders, such as a cancer, bacterial infection, fungalinfection, and immune deficiency disorder.

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating cancer, include, for example, mitomycin, tretinoin,ribomustin, gemcitabine, vincristine, etoposide, cladribine,mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin,nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed,daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane,nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone,aminoglutethimide, amsacrine, proglumide, elliptinium acetate,ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin,nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane,sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine,picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride,oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol,formestane, interferon-alpha, interferon-2 alpha, interferon-beta,interferon-gamma, colony stimulating factor-1, colony stimulatingfactor-2, denileukin diftitox, interleukin-2, and leutinizing hormonereleasing factor.

An additional class of agents that may be used as part of a combinationtherapy in treating cancer is immune checkpoint inhibitors (alsoreferred to as immune checkpoint blockers). Immune checkpoint inhibitorsare a class of therapeutic agents that have the effect of blockingimmune checkpoints. See, for example, Pardoll in Nature Reviews Cancer(2012) vol. 12, pages 252-264. Exemplary immune checkpoint inhibitorsinclude agents that inhibit one or more of (i) cytotoxicT-lymphocyte-associated antigen 4 (CTLA4), (ii) programmed cell deathprotein 1 (PD1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4, and (vii)TIM3. The CTLA4 inhibitor Ipilumumab has been approved by the UnitedStates Food and Drug Administration for treating melanoma.

Yet other agents that may be used as part of a combination therapy intreating cancer are monoclonal antibody agents that targetnon-checkpoint targets (e.g., herceptin) and non-cytoxic agents (e.g.,tyrosine-kinase inhibitors).

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating a bacterial infection, include, for example,amoxicillin, azithromycin, cefazolin, ceftriaxone, cefuroxime,cephalexin, ciprofloxacin, clindamycin, doxycycline, levofloxacin,linezolid, metronidazole, moxifloxacin, and penicillin.

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating a fungal infection, include, for example,2-phenylphenol; 8-hydroxyquinoline sulfate; acibenzolar-S-methyl;aldimorph; amidoflumet; ampropylfos; ampropylfos-potassium; andoprim;anilazine; azaconazole; azoxystrobin; benalaxyl; benodanil; benomyl;benthiavalicarb-isopropyl; benzamacril; benzamacril-isobutyl; bilanafos;binapacryl; biphenyl; bitertanol; blasticidin-S; bromuconazole;butylamine; calcium polysulphide; capsimycin; captafol; captan;carbendazim; carboxin; carpropamid; carvone; chinomethionat;chlobenthiazone; chlorfenazole; chloroneb; chlorothalonil; chlozolinate;clozylacon; cyazofamid; cyflufenamid; cymoxanil; cyproconazole;cyprodinil; cyprofuram; Dagger G; debacarb; dichlofluanid; dichlone;dichlorophen; diclocymet; diclomezine; dicloran; diethofencarb;difenoconazole; diflumetorim; dimethirimol; dimethomorph; dimoxystrobin;diniconazole; diniconazole-M; dinocap; diphenylamine; dipyrithione;ditalimfos; dithianon; dodine; drazoxolon; edifenphos; epoxiconazole;ethaboxam; ethirimol; etridiazole; famoxadone; fenamidone; fenapanil;fenarimol; fenbuconazole; fenfuram; fenhexamid; fenitropan; fenoxanil;fenpiclonil; fenpropidin; fenpropimorph; ferbam; fluazinam;flubenzimine; fludioxonil; flumetover; flumorph; fluoromide;fluoxastrobin; fluquinconazole; flurprimidol; flusilazole;flusulphamide, hexaconazole; hymexazole; imazalil; imibenconazole;iminoctadine triacetate; iminoctadine tris(albesil); iodocarb;ipconazole; iprobenfos; iprodione; iprovalicarb; irumamycin;isoprothiolane; isovaledione; kasugamycin; kresoxim-methyl; oxyfenthiin;paclobutrazole; pefurazoate; penconazole; pencycuron; phosdiphen;phthalide; picoxystrobin; piperalin; polyoxins; polyoxorim; probenazole;prochloraz; procymidone; propamocarb; propanosine-sodium; propiconazole;propineb; proquinazid; prothioconazole; pyraclostrobin; pyrazophos;pyrifenox; pyrimethanil; pyroquilon; pyroxyfur; pyrrolenitrine;tetraconazole; thiabendazole; thicyofen; thifluzamide;thiophanate-methyl; thiram; tioxymid; tricyclazole; tridemorph;trifloxystrobin; triflumizole; triforine; triticonazole; uniconazole;validamycin A; vinclozolin; zineb; ziram; and zoxamide.

The amount of dihydro-2H-benzo[b][1,4]oxazine sulfonamide or relatedcompound (e.g., a compound of Formula I, I-A, I-B, II, II-A, II-B, II-C,or other compounds in Section I) and additional therapeutic agent andthe relative timing of administration may be selected in order toachieve a desired combined therapeutic effect. For example, whenadministering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.Further, for example, a dihydro-2H-benzo[b][1,4]oxazine sulfonamide orrelated compound (e.g., a compound of any one of Formula I, I-A, I-B,II, II-A, II-B, II-C, or other compounds in Section I) may beadministered during a time when the additional therapeutic agent(s)exerts its prophylactic or therapeutic effect, or vice versa.

The doses and dosage regimen of the active ingredients used in thecombination therapy may be determined by an attending clinician. Incertain embodiments, the dihydro-2H-benzo[b][1,4]oxazine sulfonamide orrelated compound (e.g., a compound of any one of Formula I, I-A, I-B,II, II-A, II-B, II-C, or other compounds in Section I) and theadditional therapeutic agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating thedisorder. In other embodiments, the dihydro-2H-benzo[b][1,4]oxazinesulfonamide or related compound (e.g., a compound of any one of FormulaI, I-A, I-B, II, II-A, II-B, II-C, or other compounds in Section I) andthe additional therapeutic agent(s) are administered in doses lower thanthe doses commonly employed when such agents are used as monotherapy fortreating the disorder. In certain embodiments, thedihydro-2H-benzo[b][1,4]oxazine sulfonamide or related compound (e.g., acompound of any one of Formula I, I-A, I-B, II, II-A, II-B, II-C, orother compounds in Section I) and the additional therapeutic agent(s)are present in the same composition, which is suitable for oraladministration.

In certain embodiments, the dihydro-2H-benzo[b][1,4]oxazine sulfonamideor related compound (e.g., a compound of any one of Formula I, I-A, I-B,II, II-A, II-B, II-C, or other compounds in Section I) and theadditional therapeutic agent(s) may act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of the dihydro-2H-benzo[b][1,4]oxazine sulfonamide orrelated compound (e.g., a compound of any one of Formula I, I-A, I-B,II, II-A, II-B, II-C, or other compounds in Section I), apharmaceutically acceptable carrier, vehicle or diluent, and optionallyat least one additional therapeutic agent listed above.

IV. Pharmaceutical Compositions and Dosing Considerations

As indicated above, the invention provides pharmaceutical compositions,which comprise a therapeutically-effective amount of one or more of thecompounds described above, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents. Thepharmaceutical compositions may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: (1) oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

The invention further provides a unit dosage form (such as a tablet orcapsule) comprising a dihydro-2H-benzo[b][1,4]oxazine sulfonamide orrelated compound described herein in a therapeutically effective amountfor the treatment of a medical disorder described herein.

Examples

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.Starting materials described herein can be obtained from commercialsources or may be readily prepared from commercially available materialsusing transformations known to those of skill in the art.

Example 1-Synthesis of(S,E)-5-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

Part I—Synthesis of dimethyl (R)-2-hydroxypentanedioate

To a mixture of (2R)-5-oxotetrahydro-2-furancarboxylic acid (25 g, 192mmol) in methanol (300 mL) was added concentrated hydrochloric acid (0.5mL) and the mixture was refluxed overnight then cooled to ambienttemperature. Excess solid sodium bicarbonate (4 g) was added slowly andthe mixture was slurried for 20 minutes. Then, the mixture was filteredand concentrated to obtain dimethyl (R)-2-hydroxypentanedioate (34.7 g,100%).

Part II—Synthesis of dimethyl(S)-2-(4-bromo-2-nitrophenoxy)pentanedioate

To a solution of dimethyl (R)-2-hydroxypentanedioate (33.8 g, 192 mmol),4-bromo-2-nitrophenol (50.2 g, 230 mmol), and triphenylphosphine (60.4g, 230 mmol) in dichloromethane (300 mL) with activated molecular sievesat 0° C. was added a solution of diisopropyl azodicarboxylate (45.4 mL,230 mmol) in dichloromethane (50 mL) dropwise. This mixture was stirredat 0° C. for 20 minutes, then at ambient temperature overnight. Theresulting mixture was concentrated and the triphenylphosphine oxideremoved by filtration through a large pad of silica gel, eluting withdichloromethane (˜6 L). The eluted material was a mixture of theintended product and a small amount of residual phenol. According, theeluted material was redissolved in ethyl acetate, washed four times with1M sodium hydroxide, then washed with brine, dried (Na₂SO₄), andconcentrated to yield dimethyl(S)-2-(4-bromo-2-nitrophenoxy)pentanedioate (62.84 g, 87%) as a clearoil.

Part III—Synthesis of methyl(S)-3-(6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

A flask equipped with a mechanical stirrer was charged with dimethyl(S)-2-(4-bromo-2-nitrophenoxy)pentanedioate (62.84 g, 167 mmol) andacetic acid (500 mL), followed by powdered iron (46.7 g, 835 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 2hours, and then filtered hot through a pad of celite, washing with ethylacetate (900 mL). The filtrates were combined and washed three timeswith water, washed with brine, dried (Na₂SO₄) and concentrated to yieldmethyl(S)-3-(6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(48.06 g, 92%) as a white solid.

Part IV—Synthesis of methyl(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To methyl(S)-3-(6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(24.46 g, 77.9 mmol) in anhydrous tetrahydrofuran (200 mL) at 0° C. wasadded borane-methyl sulfide complex (19.5 mL, 195 mmol) dropwise. Thismixture was heated to 50° C. for 1 hour. Then, the reaction mixture wascooled to 0° C., then carefully quenched by adding methanol (150 mL).The resulting mixture was re-heated to 60° C. for 60 minutes, thencooled and concentrated. The resulting residue was partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography eluting with a gradient of 5-50% ethyl acetate in hexanesto yield methyl(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (17.97g, 77%) as a white solid.

Part V—Synthesis of (S)-methyl3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To a solution of(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (10.0g, 33.3 mmol) in pyridine (60 mL) was added3-(trifluoromethyl)-benzenesulfonyl chloride (8.96 g, 36.6 mmol). Themixture was heated at 50° C. for four hours, then the mixture was cooledand concentrated. The resulting residue was partitioned between ethylacetate and 1N HCl. The organic layer was washed twice with 1N HCl, thenwashed with brine, and dried (Na₂SO₄). Activated charcoal was added,slurried, then filtered through celite. The filtrate was concentratedonto a small amount of silica gel and the residue was purified via MPLCeluting with a gradient of ethyl acetate in hexanes. The major UV activecomponent was concentrated to afford (S)-methyl3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(14.75 g, 87%).

Part VI—Synthesis of 1-chloro-2-ethynyl-3-fluorobenzene

2-Chloro-6-fluorobenzaldehyde (2.00 g, 12.61 mmol) was dissolved inmethanol (84 mL), and dimethyl (diazomethyl)phosphonate (2.39 mL, 15.77mmol) was added followed by potassium carbonate (4.36 g, 31.53 mmol).The reaction mixture was stirred at room temperature overnight. Then,the crude mixture was diluted with methyl tert-butyl ether, washed withwater, washed with brine, dried (Na₂SO₄), and concentrated to afford1-chloro-2-ethynyl-3-fluorobenzene (1.83 g, 94%). ¹H-NMR (400 MHz,DMSO-d₆) δ 7.45 (m, 2H), 7.32 (t, 1H), 4.86 (s, 1H).

Part VII—Synthesis of(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Bis(pinacolato)diborane (5.82 g, 22.92 mmol), copper (I) chloride (0.21g, 2.08 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.21g, 2.08 mmol) were suspended in THF (208 mL) and the mixture wasdegassed with nitrogen, and stirred for five minutes. A solution ofsodium tert-butoxide (2.202 g, 22.92 mmol) in the minimum amount of THFwas added, and the mixture stirred for an additional five minutes.1-Chloro-2-ethynyl-3-fluorobenzene (3.22 g, 20.83 mmol) and methyliodide (11.83 g, 83.33 mmol) were added to the reaction mixture, and theresulting mixture was stirred at room temperature overnight. Then, thecrude product mixture was concentrated onto silica gel and purified byMPLC eluting with a gradient of 0-5% ethyl acetate in hexanes to afford(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.41 g, 39%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.31 (m, 2H), 7.20 (t, 1H),5.18 (s, 1H), 2.15 (s, 3H), 1.23 (s, 12H).

Part VIII—Synthesis of (S,E)-methyl3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

A mixture of (S)-methyl3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(7.46 g, 14.7 mmol),(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6.09 g, 20.5 mmol), potassium carbonate (2.84 g, 20.5 mmol) in dioxane(80 mL) and water (20 mL) was degassed and was placed under anatomosphere of nitrogen.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1.12 g, 1.47 mmol) was added to the mixture andthe mixture was heated to 70° C. for five hours. Toluene (100 mL) and a20% solution of sodium bisulfite in water (50 mL) were added to thereaction mixture and the resulting mixture was stirred at 60° C. for anadditional fifteen minutes. Then, the mixture was cooled andsubsequently diluted with toluene (150 mL). The organic layer was washedwith a 20% aqueous solution of sodium bisulfite, water, then brine. Theorganic solution was dried (Na₂SO₄), and activated charcoal was added.The resulting mixture was slurried, and filtered through a pad ofcelite. The filtrate was concentrated onto a small amount of silica geland the residue was purified by MPLC eluting with a gradient of 0-30%ethyl acetate in hexanes to afford (S,E)-methyl3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(8.31 g, 94%).

Part IX—Synthesis of(S,E)-5-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

A solution of (S,E)-methyl3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(70 mg, 0.117 mmol) and hydrazine (37.5 mg, 1.17 mmol) in methanol (2mL) was heated to 50° C. for two hours. After allowing to cool, themixture was concentrated to afford(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanehydrazidewhich was used without purification. To a solution of this hydrazide inTHF (2 mL) at 0° C. was added diisopropylethylamine (30 mg, 0.23 mmol)followed by triphosgene (20 mg, 0.058 mmol). This mixture was stirred at0° C. for ten minutes, and at room temperature for two hours. Themixture was partitioned between ethyl acetate and water, washed withbrine, dried (Na₂SO₄), and concentrated onto silica gel. The product waspurified by MPLC eluting with a gradient of ethyl acetate in hexanes toafford(S,E)-5-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one(35 mg, 48%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.04 (s,1H), 8.07 (m, 2H), 7.97 (s, 1H), 7.84 (d, 1H, J=8.1 Hz), 7.67 (d, 1H,J=1.7 Hz), 7.37 (m, 2H), 7.25 (m, 1H), 7.10 (m, 1H), 6.84 (d, 1H, J=8.4Hz), 6.36 (s, 1H), 4.40 (dd, 1H, J1=14.1 Hz, J2=0.9 Hz), 3.53 (m, 1H),3.4 (m, 2H), 2.63 (m, 2H), 2.07 (s, 3H), 1.95 (m, 1H), 1.80 (m, 1H).(ES, m/z): (M+Na)⁺ 645.97, 647.95.

Example 2—Synthesis of(S,E)-2-(2-(2H-tetrazol-5-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Part I—Synthesis of (R)-3-(4-bromo-2-nitrophenoxy)dihydrofuran-2(3H)-one

4-Bromo-2-nitrophenol (3 g, 13.76 mmol),(3R)-3-hydroxytetrahydrofuran-2-one (1.405 g, 13.76 mmol), andtriphenylphosphine (4.33 g, 16.51 mmol) were suspended indichloromethane (36 mL), and diisopropylazodicarboxylate (3.25 mL, 16.5mmol) was added dropwise. The reaction mixture was stirred at roomtemperature for one hour, washed with water, dried (Na₂SO₄), andconcentrated onto silica gel. The residue on the silica gel was purifiedby MPLC (2 columns: first, dichloromethane; second, a gradient ofEtOAc/hexanes) affording(R)-3-(4-bromo-2-nitrophenoxy)dihydrofuran-2(3H)-one as a white solid(1.93 g, 46%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.86 (d, 1H),7.47 (d, 1H), 5.55 (t, 1H), 4.42 (m, 1H), 4.26 (m, 1H), 2.75 (m, 1H),2.30 (m, 1H).

Part II—Synthesis of(S)-6-bromo-2-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

(R)-3-(4-Bromo-2-nitrophenoxy)dihydrofuran-2(3H)-one (1.93 g, 6.39 mmol)was dissolved in acetic acid and powdered iron (1.784 g, 31.95 mmol) wasadded. The resulting mixture was heated to 70° C. for two hours. Then,the resulting suspension was filtered through a pad of celite, and thepad was washed with ethyl acetate. The combined filtrates werepartitioned between ethyl acetate and water, and the organic phase waswashed a second time with water, washed with brine, and concentrated toprovide a residue. The residue was purified via MPLC eluting with agradient of 15-70% ethyl acetate in hexanes to afford(S)-6-bromo-2-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as awhite solid (1.32 g, 76%). ¹H-NMR (400 MHz, DMSO-d₆) δ 10.73 (bs, 1H),7.04 (d, 1H), 6.98 (s, 1H), 6.90 (d, 1H), 4.62 (m, 2H), 3.53 (m, 2H),1.91 (m, 1H), 1.88 (m, 1H).

Part III—Synthesis of(S)-2-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol

(S)-6-Bromo-2-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1.32 g,4.85 mmol) was dissolved in anhydrous THF (49 mL) under nitrogen atambient temperature and borane-dimethylsulfide complex (1.47 g, 19.41mmol) was added dropwise. The reaction mixture was heated to reflux for90 minutes. Then, the reaction vessel containing the reaction mixturewas cooled in an ice bath and subsequently methanol was added to thereaction mixture to quench the reaction. The resulting solution washeated to reflux for 20 minutes, and then concentrated to provide aresidue. The residue was partitioned between ethyl acetate and water,washed with brine, dried (Na₂SO₄), and concentrated to provide crudeproduct. The crude product was purified by MPLC eluting with a gradientof 15-70% ethyl acetate in hexanes to afford(S)-2-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol (1.05g, 84%).

Part IV—Synthesis of(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

(S)-2-(6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol (0.28g, 1.085 mmol), tert-butyldimethylchlorosilane (0.196 g, 1.302 mmol),and imidazole (0.148 g, 2.17 mmol) were dissolved in DMF (4 mL), and thereaction mixture was stirred at room temperature overnight. Next, thereaction mixture was partitioned between water and ethyl acetate, andthe organic layer was washed twice more with water, washed with brine,dried (Na₂SO₄), and concentrated onto silica gel. The residue on thesilica gel was purified by MPLC eluting with a gradient of 5-30% ethylacetate in hexanes to afford(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.19 g, 47%). ¹H-NMR (400 MHz, DMSO-d₆) δ 6.66 (s, 1H), 6.52 (s, 2H),6.06 (bs, 1H), 4.02 (q, 1H), 3.72 (m, 2H), 3.33 (m, 1H), 2.94 (m, 1H),1.70 (q, 2H), 0.82 (s, 9H), 0.01 (s, 6H).

Part V—Synthesis of(S)-2-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol

(S)-6-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(1.04 g, 2.79 mmol), 3-(trifluoromethyl)benzenesulfonyl chloride (1.025g, 4.19 mmol), and potassium carbonate (0.772 g, 5.586 mmol) weresuspended in acetone (28 mL), and the mixture was shaken at roomtemperature for 18 hours. Then, the crude material was filtered, and thefiltrate was concentrated onto silica gel and purified by chromatographydelivering(S)-2-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol(1.61 g, 99%). It is noted that the silyl protecting group did nothydrolyze immediately, but after several days at room temperatureformation of the alcohol was observed. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.11(d, 1H), 7.95 (m, 2H), 7.84 (t, 1H), 7.78 (s, 1H), 7.25 (d, 1H), 6.80(d, 1H), 4.56 (s, 1H), 3.39 (d, 1H), 3.41 (m, 3H), 3.28 (m, 1H), 1.63(m, 2H).

Part VI—Synthesis of(S)-2-(6-Bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl4-methylbenzenesulfonate

(S)-2-(6-Bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-ol(0.13 g, 0.28 mmol) was dissolved in dichloromethane (6 mL) andtriethylamine (0.058 mL, 0.42 mmol) was added followed by tosyl chloride(56 mg, 0.293 mmol). The reaction mixture was stirred at roomtemperature overnight. Then, additional tosyl chloride (56 mg, 0.293mmol) and triethylamine (0.060 mL) were added, and the reaction mixturewas stirred for one additional day. Then, the crude solution was washedwith dilute HCl, washed with brine, dried (Na₂SO₄), and concentratedonto silica gel for purification by chromatography to afford(S)-2-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl4-methylbenzenesulfonate as a white solid (0.14 g, 81%). ¹H-NMR (400MHz, DMSO-d₆) δ 8.12 (d, 1H), 7.98 (m, 2H), 7.87 (t, 1H), 7.76 (s, 1H),7.59 (d, 2H), 7.33 (d, 2H), 7.24 (dd, 1H), 6.54 (d, 1H), 4.33 (dd, 1H),4.08 (m, 1H), 4.00 (m, 1H), 3.24 (m, 2H), 2.32 (s, 3H), 1.97 (m, 1H),1.70 (m, 1H).

Part VII—Synthesis of(S)-3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

(S)-2-(6-Bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl4-methylbenzenesulfonate (0.14 g, 0.226 mmol) was dissolved in DMSO (1mL) and potassium cyanide (0.016 g, 0.248 mmol) was added. After onehour, additional potassium cyanide (17 mg) was added, and stirring wascontinued overnight. Then, the crude material was then partitionedbetween water and ethyl acetate. The organic phase was washed a secondtime, then washed with brine, dried (Na₂SO₄), and concentrated to afford(S)-3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(0.09 g, 84%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.09 (d, 1H), 8.00 (m, 2H),7.84 (t, 1H), 7.78 (s, 1H), 7.27 (d, 1H), 6.82 (d, 1H), 4.40 (d, 1H),3.37 (m, 2H), 2.56 (m, 2H), 1.92 (m, 1H), 1.72 (m, 1H).

Part VIII—Synthesis of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

(S)-3-(6-Bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(40 mg, 0.084 mmol),(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(25 mg, 0.084 mmol), THF (3 mL), and sodium hydroxide (10 mg, 0.252mmol) were combined in a vial, and the mixture was degassed by bubblingnitrogen. Tetrakis(triphenylphosphine)palladium (10 mg, 0.008 mmol) wasadded to the reaction mixture, and the resulting mixture was shaken at70° C. overnight. Then, the crude mixture was partitioned between waterand ethyl acetate. The organic phase was then washed with brine, dried(Na₂SO₄), and concentrated onto silica gel and purified bychromatography to afford(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrileas a yellow oil (31 mg, 65%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.03 (m, 3H),7.82 (m, 2H), 7.67 (s, 1H), 7.35 (m, 4H), 7.11 (d, 1H), 6.89 (d, 1H),6.38 (s, 1H), 4.42 (d, 1H), 3.40 (m, 3H), 2.60 (m, 3H), 2.07 (s, 3H),1.96 (m, 2H), 1.78 (m, 2H), 1.20 (m, 2H), 1.02 (s, 3H).

Part XI—Synthesis of(S,E)-2-(2-(2H-tetrazol-5-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

In a reaction tube were combined(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(110 mg, 0.195 mmol), dibutyltin oxide (4.8 mg, 0.019 mmol) andtrimethylsilyl azide (44.9 mmol, 0.389 mmol) in anhydrousdimethoxyethane (2 mL). The tube was sealed and the mixture was heatedat 140° C. for two hours, then cooled, and concentrated. The residue wasfirst purified by MPLC eluting with a gradient of ethyl acetate andhexanes. The fractions containing the major UV active component wereconcentrated and the residue was further purified by reverse phase HPLCto afford of(S,E)-2-(2-(2H-tetrazol-5-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(15 mg, 12%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.05 (m, 2H), 7.97 (s, 1H),7.82 (m, 1H). 7.67 (s, 1H), 7.38 (m, 2H), 7.25 (m, 1H), 7.14 (m, 1H),6.84 (m, 1H), 6.38 (s, 1H), 4.42 (m, 1H), 3.60 (m, 1H), 3.45 (m, 2H),3.0 (m, 2H), 2.1 (s, 3H), 1.98 (m, 2H). (ES, m/z): (M−H)⁻ 606.32,608.30.

Example 3—Synthesis of(R,E)-3-((7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)oxy)-1,2,4-oxadiazol-5(4H)-one

Part I—Synthesis of (E)-ethyl 3-(4-methoxy-2-nitrophenyl)acrylate

A mixture of 1-iodo-4-methoxy-2-nitrobenzene (279 mg, 1.00 mmol),palladium acetate (11.2 mg, 0.05 mmol), triethylamine (202 mg, 2.00mmol), and ethyl acrylate (110 mg, 1.10 mmol) was heated to reflux forfive hours. Then, the mixture was cooled, concentrated and diluted withethyl acetate. The resulting organic mixture was washed with water, thenbrine, dried (Na₂SO₄) and concentrated. The resulting residue waspurified via MPLC eluting with 3:1 hexane:ethyl acetate to afford(E)-ethyl 3-(4-methoxy-2-nitrophenyl)acrylate (201 mg, 80%) as a yellowsolid.

Part II—Synthesis of (2R,3S)-ethyl2,3-dihydroxy-3-(4-methoxy-2-nitrophenyl)propanoate

To a solution of (E)-ethyl 3-(4-methoxy-2-nitrophenyl)acrylate (5 g,19.90 mmol) in tert-butanol/water (1:1) (150 mL) was addedmethanesulfonamide (2 g, 21.03 mmol) followed by the addition ofAD-mix-α (16.4 g, 21.05 mmol) in several portions at 0° C. The reactionmixture was stirred overnight at room temperature and then quenched bythe addition of saturated aqueous NaHSO₃ (200 mL). The resulting mixturewas extracted three times with ethyl acetate, and the combined organiclayers were concentrated. The resulting residue was purified via MPLCeluting with ethyl acetate/petroleum ether (4:1). Concentration of themajor UV active component afforded (2R,3S)-ethyl2,3-dihydroxy-3-(4-methoxy-2-nitrophenyl)propanoate (4.95 g, 87%) as ayellow solid.

Part III—Synthesis of (4R,5S)-ethyl5-(4-methoxy-2-nitrophenyl)-1,3,2-dioxathiolane-4-carboxylate 2-oxide

To a stirred solution of ethyl(2R,3S)-2,3-dihydroxy-3-(4-methoxy-2-nitrophenyl)propanoate (5 g, 17.53mmol) and triethylamine (5.3 g, 52.38 mmol) in dichloromethane (150 mL)at 0° C. was added thionyl chloride (2.7 g, 22.69 mmol) dropwise. Themixture was stirred for 1 hour, and then quenched by the addition ofwater. The resulting mixture was extracted three times withdichloromethane. The combined organic layers were dried (Na₂SO₄) andconcentrated. The resulting residue was purified via MPLC eluting with agradient of ethyl acetate/petroleum ether (1:10-1:2). Concentration ofthe major UV active component afforded (4R,5S)-ethyl5-(4-methoxy-2-nitrophenyl)-1,3,2-dioxathiolane-4-carboxylate 2-oxide(5.2 g, 90%) as a yellow oil.

Part IV—Synthesis of (R)-7-methoxy-1,2,3,4-tetrahydroquinolin-3-ol

To a solution of (4R,5S)-ethyl5-(4-methoxy-2-nitrophenyl)-1,3,2-dioxathiolane-4-carboxylate 2-oxide(1.5 g, 4.53 mmol) in 190 proof ethanol (60 mL) at 0° C. was addedcobalt (II) chloride hexahydrate (213 mg, 0.90 mmol) followed by theaddition of sodium borohydride (1.33 g, 36.1 mmol). The mixture wasstirred overnight at room temperature. Then, the mixture was poured intoice water (100 mL), and extracted four times with ethyl acetate. Thecombined organic layers were concentrated and the resulting residue waspurified via MPLC eluting with ethyl acetate/petroleum ether (1:1) toafford (R)-7-methoxy-1,2,3,4-tetrahydroquinolin-3-ol (550 mg, 68%) as ayellow solid.

Part V—Synthesis of(R)-7-methoxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol

To a room temperature solution of(R)-7-methoxy-1,2,3,4-tetrahydroquinolin-3-ol (400 mg, 2.23 mmol) indichloromethane (12 mL) and pyridine (12 mL) was added3-(trifluoromethyl)benzene-1-sulfonyl chloride (600 mg, 2.45 mmol). Thismixture was stirred for two hours, diluted with dichloromethane andwashed twice with 1M hydrogen chloride. The organic layer was dried(Na₂SO₄) and concentrated to afford(R)-7-methoxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol(650 mg, 75%) as a colorless oil.

Part VI—Synthesis of(R)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3,7-diol

To a solution of(R)-7-methoxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol(1.1 g, 2.84 mmol) in dichloromethane (20 mL) at −78° C. was added borontribromide (11.2 g, 44.7 mmol) dropwise. The reaction mixture wasallowed to warm to room temperature and was stirred for two hours. Then,the reaction was quenched by adding water to the reaction mixture, andthe resulting mixture was extracted twice with dichloromethane. Thecombined organic layers were dried (Na₂SO₄) and concentrated. Theresulting residue was purified via MPLC eluting with petroleumether:ethyl acetate (1:1). Concentration of the major UV activecomponent afforded(R)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3,7-diol(900 mg, 85%) as a colorless oil.

Part VII—Synthesis of(R)-3-hydroxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yltrifluoromethanesulfonate

To a stirred solution of(R)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3,7-diol(800 mg, 2.14 mmol) and pyridine (676 mg, 8.55 mmol) in dichloromethane(70 mL) was added a solution of trifluoromethanesulfonic anhydride (847mg, 3.00 mmol) in dichloromethane (5 mL) dropwise. The reaction mixturewas stirred for two hours at room temperature. Then, the reactionmixture was diluted with water. The resulting mixture was extracted withdichloromethane. The organic layer was washed with water, then brine,and concentrated. The resulting residue was purified via MPLC elutingwith ethyl acetate/petroleum ether (1:10-1:3) to afford(R)-3-hydroxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yltrifluoromethanesulfonate (950 mg, 88%) as a yellow oil.

Part VIII—Synthesis of(R,E)-7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol

To a flask, which was purged and maintained with an inert atmosphere ofnitrogen, was placed a solution of(R)-3-hydroxy-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yltrifluoromethanesulfonate (400 mg, 0.79 mmol) in toluene (12 mL),ethanol (4 mL), water (2 mL),2-[(1E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(258 mg, 0.87 mmol), and potassium acetate (232 mg, 2.36 mmol).Tetrakis(triphenylphosphane) palladium (91 mg, 0.08 mmol) was added tothe reaction mixture and the mixture was stirred for three hours at 90°C. Then, the reaction mixture was cooled and was extracted three timeswith ethyl acetate. The organic layers were combined and concentrated.The resulting residue was purified via MPLC eluting with ethylacetate/petroleum ether (1:10-2:1) to afford(R,E)-7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol(215 mg, 52%) as a yellow oil. ¹H-NMR (300 MHz, CD₃OD) δ 7.93-8.05 (m,3H), 7.70-7.76 (m, 2H), 7.26-7.35 (m, 2H), 7.09-7.17 (m, 3H), 6.39 (s,1H), 4.11 (m, 1H), 3.92 (m, 1H), 3.61-3.38 (m, 1H), 2.76 (m, 1H), 2.46(m, 1H), 2.12 (s, 3H). (ES, m/z): (M+H)⁺ 526.

Part IX—Synthesis of ethylN-([[(3R)-7-[(1E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl]-1-[[3-(trifluoromethyl)benzene]sulfonyl]-1,2,3,4-tetrahydroquinolin-3-yl]oxy]methanethioyl)carbamate

To a room temperature solution of(R,E)-7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-ol(250 mg, 0.48 mmol) in chloroform (10 mL) was added ethylN-carbothioylcarbamate (0.56 mL, 4.8 mmol). The solution was stirred fortwo days at 60° C. and concentrated. The resulting residue was purifiedby MPLC eluting with a gradient of ethyl acetate/petroleum ether (0-25%)to afford ethylN-([[(3R)-7-[(1E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl]-1-[[3-(trifluoromethyl)benzene]sulfonyl]-1,2,3,4-tetrahydroquinolin-3-yl]oxy]methanethioyl)carbamate(250 mg, 80%) as a yellow oil.

Part X—Synthesis of(R,E)-3-((7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)oxy)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylamine hydrochloride (59.2 mg, 0.858 mmol) andlithium hydroxide monohydrate (20.4 mg, 0.49 mmol) in ethanol (5 mL) wasstirred for thirty minutes at 40° C. To this solution was added ethylN-([[(3R)-7-[(1E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl]-1-[[3-(trifluoromethyl)benzene]sulfonyl]-1,2,3,4-tetrahydroquinolin-3-yl]oxy]methanethioyl)carbamate(80 mg, 0.12 mmol) in ethanol (2 mL) dropwise with stirring and themixture was stirred overnight at 40° C. Then, the mixture wasconcentrated and the resulting residue was purified by Prep-HPLC elutingwith a gradient of 60% to 72% acetonitrile in water with 0.05% TFA toafford(R,E)-3-((7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)oxy)-1,2,4-oxadiazol-5(4H)-one(30 mg, 41%) as a white solid. ¹H-NMR (300 MHz, CD₃OD) δ 8.02 (d, J=9Hz, 1H), 7.95 (m, 2H), 7.75 (t, J=7.5 Hz, 1H), 7.58 (s, 1H), 7.27 (m,2H), 7.05-7.17 (m, 3H), 6.35 (s, 1H), 5.11 (m, 1H), 4.16-4.30 (m, 2H),2.85 (d, J=6 Hz, 2H), 2.06 (s, 3H). (ES, m/z): (M+H)⁺ 508.

Example 4—Synthesis of(R,E)-3-((7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)oxy)-1H-1,2,4-triazol-5(4H)-one

To a mixture of ethylN-([[(3R)-7-[(1E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl]-1-[[3-(trifluoromethyl)benzene]sulfonyl]-1,2,3,4-tetrahydroquinolin-3-yl]oxy]methanethioyl)carbamate(370 mg, 0.56 mmol), methanol (10 mL), and potassium hydroxide (3.16 mg,0.06 mmol) was added a solution of hydrazine hydrate (31 mg, 0.6 mmol)in methanol (3 mL) dropwise with stirring at 0° C. The solution wasstirred for five hours at room temperature and then concentrated. Theresulting residue was purified by Prep-HPLC eluting with a gradient of50-67% acetonitrile in water with 0.05% TFA to afford(R,E)-3-((7-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)oxy)-1H-1,2,4-triazol-5(4H)-oneas a white solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.11 (s, 1H), 7.91 (s, 1H),7.84 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.26-7.17 (m, 3H), 7.10-7.02(m, 2H), 6.42 (s, 1H), 4.97 (s, 1H), 4.28 (s, 1H), 4.21 (s, 1H), 2.94(s, 1H), 2.76 (s, 1H), 2.17 (s, 3H), 1.27 (s, 1H). (ES, m/z): (M−100)⁺508.

Example 5—Synthesis of(2R,3S)-3-((1H-imidazol-1-yl)methyl)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline

Part I—Synthesis of (R)-methyl3-(3-(trifluoromethyl)phenylsulfonamido)butanoate

To a mixture of methyl (3R)-3-aminobutanoate hydrochloride (6.10 g, 39.7mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (10.69 g, 43.7mmol) in methylene chloride (100 mL) was added diisopropylethylamine(14.4 g, 111 mmol). The mixture was stirred overnight, then partitionedbetween dichloromethane and saturated ammonium chloride. The organiclayer was washed with saturated sodium bicarbonate, then brine, anddried (Na₂SO₄) then concentrated. The resulting residue was purified byMPLC eluting with a gradient of 9:1 to 3:2 hexane:ethyl acetate toafford (R)-methyl 3-(3-(trifluoromethyl)phenylsulfonamido)butanoate(9.23 g, 71%) as a clear oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.03 (m, 3H),7.83 (t, 1H), 3.55 (q, 1H), 3.42 (s, 3H), 2.36 (d, 2H), 0.93 (d, 3H).(MS, m/z): (M+Na)⁺ 348.18.

Part II—Synthesis of (2R,3R)-methyl2-(2,4-dibromobenzyl)-3-(3-(trifluoromethyl)phenyl-sulfonamido)butanoate

To a 1M solution of lithium hexamethylsilazide in THF (75.2 mL, 75.2mmol) at −78° C. was added a solution of (R)-methyl3-(3-(trifluoromethyl)phenylsulfonamido)butanoate (11.65 g, 35.8 mmol)in THF (300 mL) dropwise. After completion of the addition, the mixturewas stirred an additional thirty minutes allowing the mixture'stemperature to rise to −40° C. Then, the mixture was cooled again at−78° C., and then a solution of 2,4-dibromo-1-(bromomethyl)benzene inTHF (60 mL) was added dropwise. The cooling bath was removed from thereaction vessel and the reaction mixture was allowed to warm to roomtemperature. Next, the reaction was quenched by addition of saturatedammonium chloride to the reaction mixture, and the resulting mixture waspartitioned between ethyl acetate and water. The organic layer wasisolated and washed with brine, dried (Na₂SO₄), and concentrated. Theresulting residue was purified by MPLC eluting with a gradient of ethylacetate and hexanes to afford (2R,3R)-methyl2-(2,4-dibromobenzyl)-3-(3-(trifluoromethyl)phenyl-sulfonamido)butanoate(12.14 g, 59%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.11 (m,3H), 8.02 (d, 1H), 7.84 (t, 1H), 7.79 (m, 1H), 7.47 (dd, 1H), 7.08 (d,1H), 3.60 (m, 1H), 3.37 (s, 3H), 2.84 (m, 2H), 2.78 (m, 1H), 0.92 (d,3H).

Part III—Synthesis of (2R,3R)-methyl7-bromo-2-methyl-1-((3-(trifluoromethyl)-phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate

A mixture of (2R,3R)-methyl2-(2,4-dibromobenzyl)-3-(3-(trifluoromethyl)phenyl-sulfonamido)butanoate(4.63 g, 8.08 mmol), copper (I) iodide (0.62 g, 3.23 mmol),N,N′-dimethylethylenediamine (0.71 g, 8.08 mmol) and potassium phosphate(5.14 g, 24.2 mmol) in toluene (80 mL) was heated at reflux overnight.Then, the reaction mixture was cooled and partitioned between ethylacetate and saturated aqueous ammonium chloride. The organic layer waswashed with brine, dried (Na₂SO₄) and concentrated. The resultingresidue was purified by MPLC eluting with a gradient of hexanes andethyl acetate to afford (2R,3R)-methyl7-bromo-2-methyl-1-((3-(trifluoromethyl)-phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(3.23 g, 81%). Note: This material contained some (2R,3R)-methyl7-iodo-2-methyl-1-((3-(trifluoromethyl)-phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylateand was used without further purification in the next step of thesynthetic procedure. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.11 (d, 1H), 7.90 (m,2H), 7.83 (t, 1H), 7.78 (s, 1H), 7.36 (d, 1H), 7.18 (d, 1H), 4.73 (m,1H), 3.61 (s, 3H), 2.75 (m, 2H), 2.24 (m, 1H), 0.91 (d, 1H).

Part IV—Synthesis of (2R,3R)-methyl7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate

To a degassed mixture of ((2R,3R)-methyl7-bromo-2-methyl-1-((3-(trifluoromethyl)-phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(3.23 g, 6.56 mmol), potassium carbonate (1.36 g, 9.84 mmol),(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.14 g, 7.22 mmol), dioxane (24 mL) and water (6 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.54 g, 0.66 mmol). The mixture was heated to 70°C. for five hours. Then, the mixture was cooled, and partitioned betweenethyl acetate and water. The organic layer was washed with brine, dried(Na₂SO₄), and concentrated. The resulting residue was purified by MPLCeluting with a gradient of 0-50% ethyl acetate in hexanes to afford(2R,3R)-methyl7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(2.69 g, 70%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.11 (m, 1H), 7.90 (m, 4H),7.64 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 7.19 (m, 1H), 6.41 (s, 1H),4.80 (m, 1H), 4.00 (q, 1H), 3.64 (s, 3H), 3.62 (s, 1H), 3.53 (s, 2H),2.80 (m, 3H), 2.35 (m, 2H), 2.11 (s, 3H), 1.97 (s, 2H), 1.15 (t, 2H),0.98 (dd, 5H). (MS, m/z): (M+Na)⁺ 604.2.

Part V—Synthesis of((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methanol

To a 1M solution of lithium aluminum hydride (5.08 mL, 5.08 mmol) wasadded dropwise a solution of (2R,3R)-methyl7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(2.69 g, 4.62 mmol) in THF (46 mL). The mixture was stirred for threehours at room temperature, and then the reaction was quenched slowly byadding sodium sulfate decahydrate (3 g) to the reaction mixture. Theresulting mixture was stirred for an additional hour, and then filtered.The filtrate was concentrated and the residue was purified by MPLCeluting with a gradient of hexanes and ethyl acetate. Concentration ofthe major UV active component afforded a residue which was furtherpurified by MPLC eluting with a gradient of 0-5% methanol indichloromethane to afford((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methanol(0.91 g, 36%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.07 (d, 1H), 7.93 (d, 1H),7.80 (m, 2H), 7.69 (s, 1H), 7.38 (m, 2H), 7.27 (m, 1H), 7.14 (m, 2H),6.40 (s, 1H), 4.70 (m, 2H), 3.27 (m, 1H), 3.19 (m, 1H), 2.27 (m, 1H),2.10 (s, 3H), 1.59 (m, 1H), 0.98 (d, 3H). (ES, m/z): (M+K)⁺ 592.14.

Part VI—Synthesis of((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methylmethanesulfonate

To a solution of((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methanol(0.91 g g, 1.64 mmol) and triethylamine (0.28 g, 2.79 mmol) indichloromethane (8 mL) was added methanesulfonyl chloride. The mixturewas stirred overnight at room temperature, and then washed with aqueouscitric acid, brine, dried (Na₂SO₄), and concentrated. The resultingresidue was purified via MPLC eluting with petroleum ether:ethyl acetate(1:1). Concentration of the major UV active component afforded((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methylmethanesulfonate (0.98 g, 94%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.08 (d,1H), 7.93 (d, 1H), 7.83 (m, 2H), 7.69 (s, 1H), 7.38 (m, 2H), 7.28 (m,1H), 7.19 (m, 2H), 6.42 (s, 1H), 4.66 (m, 1H), 4.10 (d, 2H), 3.18 (s,3H), 2.63 (dd, 1H), 2.45 (m, 1H), 2.12 (s, 3H), 1.92 (m, 1H), 1.01 (d,3H).

Part V—Synthesis of(2R,3S)-3-((1H-imidazol-1-yl)methyl)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline

To a solution of imidazole (20 mg, 0.29 mmol) in DMF (1.5 mL) at roomtemperature was added 60% sodium hydride in mineral oil (10 mg, 0.26mmol). The mixture was stirred for fifteen minutes, and((2R,3R)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methylmethanesulfonate (100 mg, 0.16 mmol) was added. The mixture was heatedat 60° C. overnight, then cooled and partitioned between ethyl acetateand water. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated. The resulting residue was purified by MPLC, eluting with agradient of 0-10% methanol in dichloromethane to afford(2R,3S)-3-((1H-imidazol-1-yl)methyl)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline(25 mg, 25%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.08 (d, 1H), 7.79 (m, 4H),7.58 (s, 1H), 7.38 (m, 2H), 7.28 (m, 1H), 7.16 (s, 2H), 6.96 (s, 1H),6.90 (s, 1H), 6.41 (s, 1H), 5.73 (s, 1H), 4.35 (m, 1H), 4.08 (m, 1H),3.92 (m, 2H), 3.15 (d, 3H), 2.40 (m, 1H), 2.12 (s, 3H), 1.77 (m, 1H),1.05 (d, 3H). (ES, m/z): (M+H)⁺ 604.33.

Example 6—Synthesis of(S,E)-3-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(70 mg, 0.124 mmol) in methanol (3 mL) was added hydroxylamine (164 mg,2.48 mmol). The mixture was heated at 60° C. overnight, then cooled andconcentrated. The resulting residue was dissolved in THF (5 mL) thencooled to 0° C. Next, diisopropylethylamine (48 mg, 372 mmol) was added,followed by triphosgene (55 mg, 186 mmol). The resulting mixture waswarmed to room temperature and stirred for two hours. Then, the mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (Na₂SO₄), and concentrated. The resultingresidue was purified by MPLC eluting with a gradient of ethyl acetate inhexanes to afford(S,E)-3-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,2,4-oxadiazol-5(4H)-one(22 mg, 27%). ¹H-NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 8.1 (m, 2H),7.97 (s, 1H), 7.84 (d, 1H), 7.68 (m, 1H), 7.38 (m, 2H), 7.25 (m, 1H),7.15 (m, 1H), 6.86 (m, 1H), 6.4 (s, 1H), 4.40 (m, 1H), 3.62 (m, 1H),3.48 (m, 1H), 2.62 (m, 2H), 2.1 (s, 3H), 1.98 (m, 1H), 1.85 (m, 1H).(ES, m/z): (M+Na)⁺ 646.27, 648.23.

Example 7—Synthesis of(S,E)-2-(2-(1H-imidazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Part I—Synthesis of(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(1.60 g, 4.30 mmol) in pyridine (15 mL) was added3-(trifluoromethyl)benzenesulfonyl chloride (1.26 g, 5.15 mmol). Themixture was stirred at 50° C. for two hours, then cooled and partitionedbetween ethyl acetate and 1N HCl. The organic layer was washed threetimes with 1N HCl, brine, and dried (Na₂SO₄). Charcoal was added to theresulting mixture, and the mixture was slurried, then filtered throughcelite. The filtrate was concentrated and the resulting residue waspurified by MPLC eluting with a gradient of ethyl acetate in hexanes toafford(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.40 g, 100%).

Part II—Synthesis of(S,E)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a degassed mixture of(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(1.78 g, 6.03 mmol), potassium carbonate (833 mg, 6.03 mmol),(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.788 g, 6.03 mmol), dioxane (25 mL) and water (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.328 g, 0.431 mmol). The mixture was heated to70° C. for five hours. Then, the mixture was cooled, and partitionedbetween ethyl acetate and saturated aqueous ammonium chloride. Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated.The resulting residue was purified by MPLC eluting with a gradient of0-50% ethyl acetate in hexanes to afford(S,E)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.40 g, 83%).

Part III—Synthesis of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethanol

To a solution of(S,E)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.40 g, 3.58 mmol) in THF (24 mL) was added a 1M solution oftetrabutylammonium fluoride (1.40 g, 5.37 mmol) in THF (5.37 mL). Themixture was stirred for 1 hour, then concentrated onto a small amount ofsilica gel. The residue was purified by MPLC eluting with a gradient of0-100% ethyl acetate in hexanes to afford(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethanol(1.55 g, 78%).

Part IV—Synthesis of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethylmethanesulfonate

Methanesulfonic anhydride (211 mg, 1.21 mmol) was added to a solution of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethanol(0.45 g, 0.81 mmol) and diisopropylethylamine (0.21 g, 1.62 mmol) indichloromethane (10 mL) at 0° C. The mixture was stirred at roomtemperature for two hours, then partitioned between dichloromethane and1N HCl. The organic layer was dried (Na₂SO₄) and concentrated to afford(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethylmethanesulfonate (0.48 g, 94%).

Part V—Synthesis of(S,E)-2-(2-(1H-imidazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Imidazole (21.5 mg, 0.315 mmol) was added to a solution of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethylmethanesulfonate (50 mg, 0.079 mmol) in DMF (0.5 mL). The mixture wasstirred at 70° C. overnight, then cooled and subsequently concentrated.The resulting residue was purified by MPLC eluting with a gradient of0-5% methanol in dichloromethane to afford(S,E)-2-(2-(1H-imidazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(26 mg, 54%). ¹H-NMR (400 MHz, CDCl₃) δ 7.82 (m, 3H), 7.75 (m, 1H), 7.58(m, 1H). 7.40 (m, 1H), 7.25-7.15 (m, 3H), 7.05 (m, 2H), 6.88 (m, 1H),6.82 (m, 1H), 6.38 (s, 1H), 4.20-4.08 (m, 3H), 3.22 (m, 2H), 2.08 (s,3H), 1.96 (m, 2H). (ES, m/z): (M+H)⁺ 606.13, 608.15.

Example 8—Synthesis of(S,E)-2-(3-(1H-imidazol-1-yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Part I—Synthesis of(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol

To(S)-3-(6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(6.4 g, 20.4 mmol) in anhydrous tetrahydrofuran (60 mL) was addedborane-methyl sulfide complex (8.2 mL, 82 mmol) and the mixture washeated to 50° C. for 2 hours. Then, the reaction mixture was cooled toambient temperature, and then carefully quenched by adding methanol (25mL) and heating to 60° C. for 20 minutes. The resulting mixture wasconcentrated, then redissolved in ethyl acetate, washed with water, thenbrine, dried with sodium sulfate, filtered and concentrated to an oil.The oil was purified by column chromatography eluting with a gradient of5-100% ethyl acetate in hexanes. Fractions containing(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol werecombined and concentrated to give a solid. (2.77 g, 50%).

Part II—Synthesis of(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of(S)-3-(6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol (3.50g, 12.9 mmol) in dichloromethane (40 mL) was added diisopropylethylamine(2.49 g, 19.3 mmol), tert-butyldimethylchlorosilane (2.33 g, 15.4 mmol),and 4-dimethylaminopyridine (0.157 g, 1.29 mmol). The mixture wasstirred at room temperature overnight. Then, the mixture was washed withaqueous 10% citric acid. The organic layer was dried (Na₂SO₄), andconcentrated. The resulting residue was purified via MPLC eluting with agradient of ethyl acetate in hexanes to afford(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(3.80 g, 76%).

Part III—Synthesis of(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(1.80 g, 4.67 mmol) in pyridine (15 mL) was added3-(trifluoromethyl)benzenesulfonyl chloride (1.37 g, 5.59 mmol). Themixture was stirred at 50° C. for two hours, then cooled and partitionedbetween ethyl acetate and 1N HCl. The organic layer was washed threetimes with 1N HCl, then brine, and dried (Na₂SO₄). Charcoal was added tothe resulting mixture, which was slurried and then filtered throughcelite. The filtrate was concentrated and the residue was purified byMPLC eluting with a gradient of ethyl acetate in hexanes to afford(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.45 g, 88%).

Part IV—Synthesis of(S,E)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a degassed mixture of(S)-6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.45 g, 4.12 mmol), potassium carbonate (800 mg, 5.77 mmol),(E)-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.71 g, 5.77 mmol), dioxane (30 mL) and water (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.31 g, 0.41 mmol). The mixture was heated to 70°C. for five hours. Then, the reaction mixture was cooled andsubsequently partitioned between ethyl acetate and saturated aqueousammonium chloride. The organic layer was washed with brine, dried(Na₂SO₄), and then concentrated. The resulting residue was purified byMPLC eluting with a gradient of 0-50% ethyl acetate in hexanes to afford(S,E)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.47 g, 88%).

Part V—Synthesis of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol

To a solution of(S,E)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(2.47 g, 3.61 mmol) in THF (24 mL) was added a 1M solution oftetrabutylammonium fluoride (1.42 g, 5.41 mmol) in THF (5.41 mL). Themixture was stirred for one hour, and then concentrated onto a smallamount of silica gel. The residue was purified by MPLC eluting with agradient of 0-100% ethyl acetate in hexanes to afford(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol(1.75 g, 85%).

Part VI—Synthesis of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propylmethanesulfonate

Methanesulfonic anhydride (240 mg, 1.39 mmol) was added to a solution of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-1-ol(0.53 g, 0.93 mmol) and diisopropylethylamine (0.24 g, 1.86 mmol) indichloromethane (10 mL) at 0° C. The mixture was stirred at roomtemperature for two hours, and then partitioned between dichloromethaneand 1N HCl. The organic layer was dried (Na₂SO₄) and concentrated toafford(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propylmethanesulfonate (0.58 g, 96%).

Part VII—Synthesis of(S,E)-2-(3-(1H-imidazol-1-yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Imidazole (26.3 mg, 0.386 mmol) was added to a solution of(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propylmethanesulfonate (50 mg, 0.077 mmol) in DMF (0.5 mL). The mixture wasstirred at 70° C. overnight, then cooled and concentrated. The resultingresidue was purified by MPLC eluting with a gradient of 0-5% methanol indichloromethane to afford(S,E)-2-(3-(1H-imidazol-1-yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(28 mg, 56%). ¹H-NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.82 (m, 2H), 7.78(m, 1H), 7.64 (m, 1H). 7.48 (m, 1H), 7.25-7.15 (m, 2H), 7.1 (m, 2H),7.02 (m, 1H), 6.90 (m, 1H), 6.82 (m, 1H), 6.38 (s, 1H), 4.24 (m, 1H),3.98 (m, 2H), 3.48 (m, 1H), 3.22 (m, 1H), 2.08 (s, 3H), 1.98 (m, 1H),1.85 (m, 1H), 1.55 (m, 2H). (ES, m/z): (M+H)⁺ 620.31, 622.33.

Example 9—Synthesis of(S,E)-2-(2-(1H-1,2,3-triazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Part I—Synthesis of(S,E)-2-(2-azidoethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethylmethanesulfonate (0.50 g, 0.79 mmol) and sodium azide (0.21 g, 3.15mmol) in DMF (5 mL) was heated to 60° C. for two hours. Then, themixture was cooled, and partitioned between ethyl acetate and water. Theorganic layer was washed with water, then brine, dried (Na₂SO₄) andconcentrated to afford(S,E)-2-(2-azidoethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.43 g, 94%).

Part II—Synthesis of(S,E)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of(S,E)-2-(2-azidoethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(200 mg, 0.344 mmol), trimethylsilylacetylene (50 mg, 0.516 mmol), andcopper (I) iodide (10 mg, 0.068 mmol) in acetonitrile (3 mL) was heatedto 70° C. overnight. Then, the mixture was concentrated and the residuewas purified via MPLC eluting with a gradient of ethyl acetate inhexanes to afford(S,E)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(210 mg, 90%).

Part III—Synthesis of(S,E)-2-(2-(1H-1,2,3-triazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of(S,E)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(210 mg, 0.31 mmol) in THF (4 mL) was added a 1M solution oftetrabutylammonium fluoride (0.16 g, 0.62 mmol) in THF (0.62 mL). Themixture was stirred at room temperature overnight then concentrated. Theresulting residue was purified via MPLC eluting with a gradient of ethylacetate in hexanes to afford(S,E)-2-(2-(1H-1,2,3-triazol-1-yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(94 mg, 50%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.06 (m, 2H), 8.00 (m, 1H),7.91 (s, 1H), 7.81 (m, 1H), 7.71 (m, 2H), 7.38 (m, 2H), 7.27 (m, 1H),7.14 (m, 1H), 6.89 (m, 1H), 6.38 (s, 1H), 4.52 (m, 2H), 4.39 (m, 1H),3.43 (m, 2H), 2.23 (m, 1H), 2.09 (m, 4H). (ES, m/z): (M+Na)⁺ 629.09,631.11.

Example 10—Synthesis of(S,E)-1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid

Part I—Synthesis of (S,E)-methyl1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of(S,E)-2-(2-azidoethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.100 mg, 0.17 mmol), methyl propiolate (14 mg, 0.17 mmol), copper (II)sulfate pentahydrate (10 mg, 0.040 mmol) and sodium L-ascorbate (10 mg,0.051 mmol) in tert-butanol (2 mL) and water (1 mL) was stirred at roomtemperature overnight. Then, the mixture was partitioned between ethylacetate and water. The organic layer was washed with water, then brine,dried (Na₂SO₄) and concentrated. The resulting residue was purified byMPLC eluting with a gradient of ethyl acetate in hexanes to afford(S,E)-methyl1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate(110 mg, 96%).

Part II—Synthesis of(S,E)-1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid

A mixture of (S,E)-methyl1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate(110 mg, 0.16 mmol) and sodium hydroxide (20 mg, 0.50 mmol) was stirredat room temperature overnight. Then, the mixture was concentrated andthe residue was partitioned between ethyl acetate and 1N HCl. Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated.The resulting residue was purified by MPLC, eluting with a gradient of0-10% methanol in dichloromethane to afford(S,E)-1-(2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic(15 mg, 14%). ¹H-NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 8.63 (s, 1H),8.01 (m, 2H), 7.90 (s, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.38 (m, 2H),7.27 (m, 1H), 7.13 (m, 1H), 6.86 (m, 1H), 6.38 (s, 1H), 4.55 (m, 2H),4.39 (m, 1H), 3.44 (m, 2H), 2.26 (m, 1H), 2.08 (m, 4H). (ES, m/z):(M+Na)⁺ 673.16, 675.16.

Example 11—Synthesis of(S,E)-5-(2-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

Part I—Synthesis of 1-chloro-2-ethynyl-3-(trifluoromethyl)benzene

To a solution of 2-chloro-6-(trifluoromethyl)benzaldehyde (10.0 g, 47.9mmol) in methanol (100 mL) was added dimethyl (diazomethyl)phosphonate(11.05 g, 57.5 mmol). The mixture was cooled to 0° C., and potassiumcarbonate (16.6 g, 119 mmol) was added. The reaction mixture was stirredat room temperature overnight. The crude mixture was diluted with ether,washed with water, washed with brine, dried (MgSO₄), and concentrated toafford 1-chloro-2-ethynyl-3-(trifluoromethyl)benzene (9.17 g, 93%).

Part II—Synthesis of(E)-2-(2-chloro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To [2,3-bis(1-adamantyl)imidazolidin-2-yl]-chloro-copper (0.99 g, 2.23mmol) and sodium tert-butoxide (0.215 g, 2.23 mmol) suspended in THF (40mL) was added bis(pinacolato)diboron (11.36 g, 44.7 mmol). The mixturewas stirred for 30 minutes, and a solution of1-chloro-2-ethynyl-3-(trifluoromethyl)benzene (9.15 g, 44.7 mmol) in THF(40 mL) and methanol (1.58 g, 49.2 mmol) was added. The mixture wasstirred overnight, then filtered through celite. The filtrate wasconcentrated and the residue was purified via MPLC eluting with agradient of 0-10% ethyl acetate in hexanes to afford(E)-2-(2-chloro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(11.23 g, 76%).

Part III—Synthesis of (S,E)-methyl3-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

A mixture of (S)-methyl3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(2.00 g, 3.93 mmol),(E)-2-(2-chloro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.83 g, 5.51 mmol), potassium carbonate (0.65 g, 4.72 mmol) in dioxane(40 mL) and water (6 mL) was degassed and placed under an atomosphere ofnitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (0.30 g, 0.39 mmol) was added and thereaction mixture heated to 70° C. overnight. Then, the reaction mixturewas cooled, and subsequently partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated onto a small amount of silica. The residue was purified byMPLC eluting with a gradient of 0-30% ethyl acetate in hexanes to afford(S,E)-methyl3-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(2.0 g, 80%).

Part IV—Synthesis of(S,E)-5-(2-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

A solution of (S,E)-methyl3-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(270 mg, 0.426 mmol) and hydrazine (140 mg, 4.26 mmol) in methanol (5mL) was heated to 50° C. for five hours. Then, the reaction mixture wascooled and concentrated to afford(S,E)-3-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanehydrazide,which was used without purification. To a solution of this hydrazide inTHF (5 mL) at 0° C. was added diisopropylethylamine (170 mg, 1.28 mmol)followed by triphosgene (190 mg, 0.64 mmol). The mixture was stirred at0° C. for ten minutes, and at room temperature for one hour. It then waspartitioned between ethyl acetate and water, washed with brine, dried(Na₂SO₄), and concentrated onto silica gel. The residue was purified byMPLC eluting with a gradient of 20-60% ethyl acetate in hexanes toafford(S,E)-5-(2-(6-(2-chloro-6-(trifluoromethyl)styryl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one(140 mg, 37%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.04 (s,1H), 8.1 (m, 2H), 7.98 (s, 1H), 7.84 (m, 2H), 7.78 (m, 2H), 7.55 (m,1H), 7.38 (m, 1H), 6.98 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 4.41 (m,1H), 3.64 (m, 1H), 3.42 (m, 1H), 2.68 (m, 2H), 1.98 (m, 1H), 1.82 (m,1H). (ES, m/z): (M+Na)⁺ 682.15, 684.13.

Example 12—Synthesis of1-((2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-imidazol-2(3H)-one

Part I—Synthesis of(E)-2-(2-fluoro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To [2,3-bis(1-adamatyl)imidazolidin-2-yl]-chloro-copper (0.21 g, 0.49mmol) and sodium tert-butoxide (0.47 g, 0.49 mmol) suspended in THF (40mL) was added bis(pinacolato)diboron (2.50 g, 9.83 mmol). The mixturewas stirred for 30 minutes, and a solution of1-chloro-2-ethynyl-3-(trifluoromethyl)benzene (9.15 g, 44.7 mmol) in THF(40 mL) and methanol (0.35 g, 11 mmol) was added. The mixture wasstirred overnight, then filtered through celite. The filtrate wasconcentrated and the residue was purified by MPLC eluting with agradient of 0-10% ethyl acetate in hexanes to afford(E)-2-(2-fluoro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.55 g, 50%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.58 (m, 4H), 7.23 (d, 1H),6.13 (d, 1H), 1.22 (s, 12H).

Part II—Synthesis of (2R,3R)-methyl7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate

A mixture of methyl(2R,3R)-6-bromo-3-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate,(E)-2-(2-fluoro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.55 g, 4.91 mmol), potassium carbonate (0.93 g, 6.7 mmol) in dioxane(36 mL) and water (9 mL) was degassed and was placed under anatomosphere of nitrogen.[1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (0.37 g, 0.45 mmol) was added and the mixture washeated to 70° C. overnight. After allowing the mixture to cool, themixture was partitioned between ethyl acetate and water. The organiclayer was isolated and washed with brine, dried (Na₂SO₄) andconcentrated onto a small amount of silica gel. The residue was purifiedby MPLC eluting with a gradient of 0-30% ethyl acetate in hexanes toafford (2R,3R)-methyl7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(2.0 g, 74%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.10 (m, 1H), 7.87 (m, 4H),7.63 (m, 2H), 7.56 (m, 1H), 7.39 (m, 1H), 7.23 (m, 2H), 7.02 (d, 1H),4.80 (m, 1H), 3.63 (d, 3H), 2.80 (m, 2H), 2.35 (m, 1H), 0.95 (m, 3H).(ES, m/z): (M+Na)⁺ 624.38.

Part IV—Synthesis of(2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylicacid

A mixture of (2R,3R)-methyl7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate(2.0 g, 3.32 mmol), sodium hydroxide (0.27 g, 6.65 mmol), water (11 mL),and THF (22 mL) was stirred at room temperature overnight. Then, thereaction mixture was acidified to pH 2 with 1N HCl, and then extractedwith ethyl acetate. The organic layer was dried (Na₂SO₄) andconcentrated. The resulting residue was purified by MPLC, eluting with agradient of 0-10% methanol in dichloromethane to afford(2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylicacid (1.77 g, 82%). ¹H-NMR (400 MHz, DMSO-d₆) δ 12.85 (bs, 1H), 8.10 (m,1H), 7.95 (t, 1H), 7.84 (m, 3H), 7.64 (m, 1H), 7.54 (m, 1H), 7.38 (m,1H), 7.22 (m, 2H), 7.05 (m, 1H), 4.56 (m, 1H), 3.57 (m, 1H), 2.75 (m,2H), 2.22 (m, 1H), 1.73 (m, 1H), 0.96 (m, 3H). (MS, m/z): (M+Na)⁺610.29.

Part IV—Synthesis of1-((2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-imidazol-2(3H)-one

A solution of(2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylicacid (100 mg, 0.17 mmol), diphenylphosphonic azide (51 mg, 0.187 mmol),triethylamine (20 mg, 0.20 mmol), toluene (2 mL) and molecular sieveswas heated to 95° C. for two hours. After allowing the reaction mixtureto cool, aminoacetaldehyde diethyl acetal (30 mg, 0.23 mmol) was addedand the mixture was heated at 70° C. overnight. Then, the mixture wascooled and subsequently partitioned between ethyl acetate and 2N HCl.The organic phase was dried (Na₂SO₄) and concentrated. The resultingresidue was dissolved in acetonitrile (5 mL), water (2 mL) andtrifluoroacetic acid (2 mL) and stirred at room temperature overnight.Then, the mixture was concentrated and the resulting residue waspurified by MPLC eluting with a gradient of ethyl acetate in hexanes toafford1-((2R,3R)-7-((E)-2-fluoro-6-(trifluoromethyl)styryl)-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-imidazol-2(3H)-one(10 mg, 9%) as a white solid. ¹H-NMR (400 MHz, ¹H-NMR (400 MHz, DMSO-d₆)δ 10.14 (s, 1H), 8.00 (m, 4H), 7.77 (t, 1H), 7.66 (m, 2H), 7.55 (m, 1H),7.43 (d, 1H), 7.23 (m, 2H), 7.10 (d, 1H), 6.50 (t, 1H), 6.37 (t, 1H),4.85 (m, 1H), 3.88 (m, 1H), 3.22 (m, 2H), 2.71 (m, 1H), 0.96 (d, 3H).(ES, m/z): (M+H)⁺ 626.11.

Example 13—Synthesis of(S,E)-5-((6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one

Part I—Synthesis of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid

To a solution of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethanol(0.45 g, 0.81 mmol) in acetone (20 mL) was added Jones' reagent dropwiseuntil a red color persisted. The reaction mixture was held at roomtemperature for an additional thirty minutes. Then, isopropanol (1 mL)was added and the mixture was filtered through celite. The filtrate wasconcentrated, and the residue was partitioned between ethyl acetate and1M HCl. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated to afford(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (440 mg, 95%).

Part II—Synthesis of (S,E)-methyl2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

A mixture of(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (380 mg, 0.67 mmol), potassium carbonate (180 mg, 1.33 mmol) andiodomethane (280 mg, 2.00 mmol) was stirred at room temperature forthree hours. Then, the mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water, then brine, dried(Na₂SO₄), and concentrated to afford (S,E)-methyl2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(300 mg, 77%).

Part III—Synthesis of(S,E)-5-((6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one

A solution of (S,E)-methyl2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(100 mg, 0.17 mmol) and hydrazine (50 mg, 1.6 mmol) in methanol (3 mL)was heated to 60° C. overnight. The mixture was cooled then concentratedto afford(S,E)-2-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetohydrazide,which was used without purification. To a solution of this hydrazide inTHF (2 mL) at 0° C. was added triethylamine (50 mg, 0.50 mmol) followedby triphosgene (50 mg, 0.17 mmol). This mixture was stirred at 0° C. forten minutes, and at room temperature for two hours. The resultingmixture was partitioned between ethyl acetate and water, washed withbrine, dried (Na₂SO₄), and concentrated onto silica gel. The crudeproduct was purified by MPLC eluting with a gradient of ethyl acetate inhexanes to afford(S,E)-5-((6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one(32 mg, 29%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.20 (s,1H), 8.12 (m, 1H), 8.03 (m, 2H), 7.87 (m, 1H), 7.71 (m, 1H), 7.37 (m,2H), 7.27 (m, 1H), 7.13 (m, 1H), 6.88 (m, 1H), 6.39 (s, 1H), 4.57 (m,1H), 3.81 (m, 1H), 3.52 (m, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.09 (s,3H). (ES, m/z): (M+Na)⁺ 632.28, 634.29.

Example 14—Synthesis of(S,E)-5-(2-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

Part I—Synthesis of methyl3-((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-6-((E)-2-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)vinyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

A mixture of (S)-methyl3-(6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(15.35 g, 30.2 mmol), triethylamine (6.11 g, 60.4 mmol), and4,4,5-trimethyl-2-vinyl-1,3,2-dioxaborinane (6.20 g, 36.2 mmol) intoluene (300 mL) was degassed and was placed under an atomosphere ofnitrogen. Bis-(tri-tert-butyl)phosphine palladium (0.77 g, 1.51 mmol)was added and the reaction was heated to 80° C. overnight. Then, themixture was cooled and subsequently partitioned between ethyl acetateand water. The organic layer was dried (Na₂SO₄), and concentrated onto asmall amount of silica gel. The residue was purified by MPLC elutingwith a gradient of ethyl acetate in hexanes. The fractions containingthe major UV active component were concentrated to afford methyl3-((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-6-((E)-2-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)vinyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(14.52 g, 82.7%) as a thick amber oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.08(d, 1H), 7.93 (m, 2H), 7.81 (t, 1H), 7.72 (s, 1H), 7.27 (d, 1H), 7.08(d, 1H), 6.76 (d, 1H), 5.83 (d, 1H), 4.33 (d, 1H), 4.25 (m, 1H), 3.54(s, 3H), 3.39 (m, 2H), 2.39 (m, 2H), 1.90 (m, 2H), 1.73 (m, 1H), 1.45(m, 1H), 1.27 (s, 6H), 1.22 (d, 3H).

Part II—Synthesis of (S,E)-methyl3-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

A mixture of methyl3-((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-6-((E)-2-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)vinyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(1.68 g, 2.89 mmol), 2-bromo-3-chloropyridine (0.83 g, 4.33 mmol), andpotassium carbonate (1.60 g, 11.5 mmol) in toluene (1.5 mL), ethanol(0.4 mL) and water (0.5 mL) was degassed and was placed under anatomosphere of nitrogen. Tetrakistriphenylphosphine palladium (0) (0.33g, 0.289 mmol) was added and the reaction mixture was heated to 90° C.overnight. Then, the mixture was cooled and subsequently partitionedbetween ethyl acetate and water. The organic layer was dried (Na₂SO₄),and concentrated onto a small amount of silica gel. The residue waspurified by MPLC eluting with a gradient of 9:1 to 7:3 hexane:ethylacetate. The fractions containing the major UV active component wereconcentrated to afford (S,E)-methyl3-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(0.66 g, 40%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.11 (m, 1H),8.02 (m, 2H), 7.82 (m, 4H), 7.49 (m, 1H), 7.39 (d, 1H), 7.30 (m, 1H),6.88 (d, 1H), 4.38 (d, 1H), 3.59 (s, 3H), 3.48 (m, 1H), 3.40 (m, 1H),2.40 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H).

Part III—Synthesis of(S,E)-5-(2-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

A solution of (S,E)-methyl3-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(330 mg, 0.58 mmol) and hydrazine (190 mg, 5.8 mmol) in methanol (6 mL)was heated to 50° C. for two hours. After allowing the reaction mixtureto cool, the mixture was concentrated to afford(S,E)-3-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanehydrazide,which was used without purification. To a solution of this hydrazide inTHF (6 mL) at 0° C. was added diisopropylethylamine (150 mg, 1.16 mmol)followed by triphosgene (90 mg, 0.29 mmol). This mixture was stirred at0° C. for ten minutes, and at room temperature for one hour. Theresulting mixture was partitioned between ethyl acetate and water,washed with brine, dried (Na₂SO₄), and concentrated onto silica gel. Theresidue was purified by MPLC eluting with a gradient of ethyl acetate inhexanes to afford(S,E)-5-(2-(6-(2-(3-chloropyridin-2-yl)vinyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one(203 mg, 56%) as a yellow solid. ¹H-NMR (400 MHz, ¹H-NMR (400 MHz,DMSO-d₆) δ 11.97 (s, 1H), 8.50 (s, 1H), 8.05 (d, 2H), 8.00 (s, 1H), 7.80(m, 4H), 7.48 (d, 1H), 7.40 (d, 1H), 7.27 (dd, 1H), 6.81 (d, 1H), 4.42(d, 1H), 3.47 (m, 2H), 2.60 (m, 2H), 1.98 (m, 1H), 1.78 (m, 1H). (MS,m/z): (M+H)⁺ 593.13.

Example 15—Preparation of Additional 1,3,4-oxadiazol-2(3H)-ones

Compounds in Table 3 were prepared based on experimental proceduresdescribed in Example 1 and the detailed description.

TABLE 3 Compd Observed No. Structure Name m/z 15A

(S,E)-5-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 604 (M + H)⁺15B

(S,E)5-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((3-ethoxy-1-ethyl- 1H-pyrazol-4-yl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 618 (M + H)⁺15C

(S,E)-5-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((1-ethyl-3-(2- hydroxyethoxy)-1H- pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one634 (M + H)⁺ 15D

(S,E)-5-(2-(4-((5-chloro-2- ethoxypyridin-3-yl)sulfonyl)-6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol-2(3H)-one 635 (M + H)⁺ 15E

(S,E)-5-(2-(4-((5-chloro-2- (2-hydroxyethoxy)pyridin-3-yl)sulfonyl)-6-(2-(2- chloro-6-fluorophenyl)prop-1-en-1-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 651 (M + H)⁺ 15F

(S,E)-5-(2-(6-(2-chloro-6- (trifluoromethyl)styryl)-4-((1-ethyl-3-(2-hydroxy- ethoxy)-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 670 (M +H)⁺ 15G

(S,E)-5-(2-(6-(2-chloro-6- (trifluoromethyl)styryl)-4-((2-ethoxy-5-(trifluoro- methyl)pyridin-3- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 705 (M +H)⁺ 15H

(S,E)-5-(2-(6-(2-chloro-6- (trifluoromethyl)styryl)-4-((3-(difluoromethoxy)- phenyl)-sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]-oxazin-2-yl)ethyl)-1,3,4- oxadiazol-2(3H)-one 658 (M + H)⁺ 15I

(S,E)-5-(2-(6-(2-chloro-6- (trifluoromethyl)styryl)-4-((3-ethoxy-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]- oxazin-2-yl)ethyl)-1,3,4- oxadiazol-2(3H)-one654 (M + H)⁺ 15J

(S,E)-5-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((2-ethoxy-5- (trifluoromethyl)pyridin-3-yl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 669 (M + H)⁺ 15K

(S,E)-5-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1- yl)-4-((3-(difluoromethoxy)-4- fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)-1,3,4-oxadiazol- 2(3H)-one 640 (M + H)⁺

Example 16—Preparation of Additional Oxygen-Linked1,2,4-Oxadiazol-5(4H)-ones

Compounds in Table 4 were prepared based on experimental proceduresdescribed in Example 3 and the detailed description.

TABLE 4 Compd Observed No. Structure Name m/z 16A

(S,E)-3-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en- 1-yl)-4-((3-(trifluoromethyl)- phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]-oxazin-2-yl)ethoxy)-1,2,4- oxadiazol-5(4H)-one 640 (M + H)⁺ 16B

(S,E)-3-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en- 1-yl)-4-((3-(difluoromethoxy)- phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]-oxazin-2-yl)ethoxy)-1,2,4- oxadiazol-5(4H)-one 638 (M + H)⁺ 16C

(S,E)-3-(2-(4-((3-chloro-1- ethyl-1H-pyrazol-4-yl)sulfonyl)-6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2- yl)ethoxy)-1,2,4-oxadiazol-5(4H)-one 624 (M + H)⁺ 16D

(S,E)-3-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((3-ethoxy-1-ethyl- 1H-pyrazol-4-yl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]-oxazin-2- yl)ethoxy)-1,2,4-oxadiazol- 5(4H)-one 634 (M +H)⁺ 16E

((S,E)-3-(2-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethoxy)-1,2,4-oxadiazol- 5(4H)-one 620 (M +H)⁺ 16F

(S,E)-3-(((6-(2-(2-chloro-6- fluorophenyl)prop-1-en-1-yl)-4-((4-fluoro-3- methoxy-phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]-oxazin-2- yl)methyl)amino)-1,2,4- oxadiazol-5(4H)-one 605(M + H)⁺

Example 17—Preparation of Additional N-linked Azoles

Compounds in Table 5 were prepared based on experimental proceduresdescribed in Examples 5, 7, 8, 9, and 10 and the detailed description.

TABLE 5 Compd Observed No. Structure Name m/z 17A

(S,E)-6-(2-(2-chloro-6- fluorophenyl)prop-1-en-1-yl)-2(2-(2-methyl-1H-imidazol-1- yl)ethyl)-4-((3- (trifluoromethyl)-phenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine 620 (M + H)⁺ 17B

(S,E)-2-(2-(1H-pyrazol-1- yl)ethyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4- ((3-(trifluoromethyl)phenyl)-sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine 606 (M + H)⁺ 17C

(S,E)-1-(3-(6-(2-(2-chloro-6- fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoro-methyl)- phenyl)sulfonyl)-3,4-dihydro-2H-benzo-[b][1,4]oxazin-2-yl)- propyl)-1H-1,2,3-triazole-4- carboxylicacid 665 (M + H)⁺ 17D

(S,E)-2-(3-(1H-1,2,3-triazol-1- yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4- ((3-(trifluoromethyl)phenyl)-sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine 621 (M + H)⁺ 17E

(S,E)-2-(3-(1H-pyrazol-1- yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4- ((3-(trifluoromethyl)phenyl)-sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine 620 (M + H)⁺ 17F

(2R,3S)-3-((1H-pyrazol-1- yl)methyl)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2- methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,3,4-tetrahydroquinoline 604 (M +H)⁺ 17G

(2R,3S)-3-((1H-1,2,3-triazol-1- yl)methyl)-7-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-2- methyl-1-((3-(trifluoro-methyl)phenyl)sulfonyl)-1,2,3,4- tetrahydroquinoline 605 (M + H)⁺

Example 18—Preparation of an Additional 1,2,4-Oxadiazol-5(4H)-oneCompound

The compound in Table 6 was prepared based on experimental proceduresdescribed in Example 6 and the detailed description.

TABLE 6 Compd Observed No. Structure Name m/z 18A

(S,E)-3-(3-(6-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoro- methyl)phenyl)-sulfonyl)- 3,4-dihydro-2H-benzo-[b][1,4]oxazin-2-yl)- propyl)-1,2,4-oxadiazol- 5(4H)-one 638 (M + H)⁺

Example 19—Preparation of an Additional Tetrazole Compound

The compound in Table 7 was prepared based on experimental proceduresdescribed in Example 2 and the detailed description.

TABLE 7 Compd Observed No. Structure Name m/z 19A

(S,E)-2-(3-(2H-tetrazo1-5- yl)propyl)-6-(2-(2-chloro-6-fluorophenyl)prop-1-en- 1-yl)-4-((3- (trifluoromethyl)-phenyl)-sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]-oxazine 622

Example 20—Biological Assays for Agonist Activity Towards RORγ

Exemplary compounds from the above Examples were tested for ability toincrease RORγ activity using (i) a RORγ-Ligand Binding Domain (LBD)TR-FRET Assay, and (ii) a Gal4-RORγ Luciferase Reporter Assay inHEK-293T Cells. Assay procedures and results are described below.

Part I—Procedures for RORγ-Ligand Binding Domain TR-FRET Assay

HIS-tagged RORγ-LBD protein was expressed in SF9 cells using abaculovirus expression system. The lysate was diluted in assay buffer(50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT, 0.01% BSA) toobtain RORγ-LBD final concentration of ˜3 nM in a 384-well assay plate(need to titrate for each batch of protein).

A stock of biotinylated-LXXLL peptide from coactivator SRC1(Biotin-CPSSHSSLTERHKILHRLLQEGSPS) was prepared in assay buffer andadded to each well (200 nM final concentration). A solution of Europiumtagged anti-HIS antibody (0.6 nM final concentration) and APC-conjugatedstreptavidin (30 nM final concentration) were also added to each well.RORγ antagonist ursolic acid was also included at a final concentrationof 2 μM. Compounds were diluted in DMSO and further diluted in assaybuffer with a final DMSO concentration at 1%.

The final assay mixture was incubated overnight at 4° C. or 2 hours atroom temperature, and the fluorescence signal was measured on anEnvision plate reader: (Excitation filter=340 nm; APC emission=665 nm;Europium emission=615 nm; dichroic mirror=D400/D630; delay time=100 μs,integration time=200 μs). 50% Effective concentration (EC₅₀) values fortest compounds were calculated from the quotient of the fluorescencesignal at 665 nm divided by the fluorescence signal at 615 nm. Thequotient of the fluorescence signals in the absence of ursolic acid ortest compound is set as 100. Max Response is defined as the upperplateau in the signal as determined by line-fit using a 4-parameterlogistic model in PRISM (GraphPad).

Part II—Procedures for Gal4-RORγ Luciferase Reporter Assay in HEK-293TCells Transfection of HEK-293 Cells

In the following protocol, HEK-293 cells were transfected with aconstruct comprising the Gal4 DNA binding domain fused to the ligandbinding domain of RORγ (Gal4-RORγ-LBD) in a pcDNA3.1neo plasmid, andalso with a reporter construct comprising pGL4.31 Gal4-luciferase(Promega). Control cells were prepared similarly using empty pcDNA3.1neoand pGL4.31 vectors.

Trans-IT reagent (Mirus, 60 μL) at room temperature was added drop wiseto OptiMEM (Invitrogen, 1.5 ml). This reagent mixture was mixed byinversion then incubated for 5 to 30 minutes at room temperature. Itthen was added to a solution of both expression vectors (5 μg each),mixed, and incubated at room temperature for about 20 minutes. HEK-293cells were harvested from incubation flasks by removing the media,treating with TrypLE Express (Invitrogen), and incubating until thecells detached from the bottom of the flask (approximately 2-5 minutes).10 Million cells were collected by centrifugation and re-suspended in 10mL of Dulbecco's Modified Eagle Medium, High Glucose (DMEM, Invitrogen)containing 10% Fetal Bovine Serum and 100 IU each of penicillin andstreptomycin. The re-suspended cells and the transfection mixture wereadded to a T75 flask, mixed and incubated overnight at 37° C. and 5%CO₂.

Assay for RORγ Activity

The cells were harvested as described above, counted, and centrifuged toobtain the desired number of cells, then re-suspended in complete growthmedia at 0.75×10⁶ cells/mL. The RORγ antagonist, ursolic acid, was addedto the cells at a final concentration of 2 μM. Cells were plated at 20μL of cell suspension/well (10,000-15,000 cells/well) in white tissueculture treated 384 well plates. Test compounds were dissolved at 10 mMin DMSO then diluted into complete growth medium to 5× the finalintended test concentration. These drug stock solutions, 5 μL/well wereadded to the tissue culture plate. The final DMSO concentration was0.2%. The plates were briefly centrifuged then incubated overnight at37° C. and 5% CO₂. To conduct the assay, the tissue culture plates wereallowed to equilibrate to room temperature and One-Glo luciferasereagent (Promega, 25 μL/well) was added. The plates were brieflycentrifuged then incubated at room temperature for 10 minutes. Theluciferase intensity was read on an Envision plate reader (PerkinElmer). RORγ activity was determined relative to controls and plotted asa function of test compound concentration using PRISM (GraphPad) todetermine a 50% effective concentration (EC₅₀). The luciferase signal inthe absence of ursolic acid or test compound is defined at 100. The MaxResponse is the upper plateau in the signal as determined by line-fitusing a 4-parameter logistic model in PRISM (GraphPad).

Part III—Results

Experimental results are provided in Table 8 below. The symbol “++++”indicates an EC₅₀ less than 0.1 μM. The symbol “+++” indicates an EC₅₀in the range of 0.1 μM to 5 μM. The symbol “++” indicates an EC₅₀ in therange of greater than 5 μM to 10 μM. The symbol “+” indicates an EC₅₀greater than 10 μM. The symbol “N/A” indicates that no data wasavailable. The symbol “****” indicates a value greater than 200. Thesymbol “***” indicates a value in the range of greater than 150 to 200.The symbol “**” indicates a value in the range of greater than 90 to150. The symbol “*” indicates a value in the range of 40 to 90.

TABLE 8 Assay Results for Sulfonamido Compounds. TR-FRET Assay Ga14-RORγAssay Max Max Compound Structure EC₅₀ Response EC₅₀ Response

++++ ** +++ **

++++ *** +++ ***

+++ *** +++ **

++++ *** ++ **

++++ *** +++ **

++++ *** +++ ***

++++ *** +++ **

++++ *** +++ **

++++ *** +++ **

++++ *** +++ ***

++++ *** +++ **

+++ *** +++ **

++++ *** +++ *

++++ *** +++ **

++++ ** +++ **

++++ *** +++ ***

++++ *** +++ **

++++ *** +++ **

++++ *** +++ ***

++++ *** +++ **

++++ *** +++ ****

++++ *** +++ **

++++ *** +++ **

++++ *** +++ **

++++ *** +++ **

++++ *** +++ **

++++ *** +++ **

++++ *** + *

+++ *** +++ **

+++ *** +++ **

++++ **** +++ **

++++ *** +++ **

++++ **** +++ **

++++ **** +++ **

+++ **** +++ **

++++ **** +++ **

++++ **** +++ **

++++ **** +++ **

++++ **** +++ **

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein: A¹ is phenylene,5-6 membered heteroarylene, or C₃₋₆ heterocycloalkylene; R¹ representsindependently for each occurrence halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C₃₋₆ cycloalkyl; R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 memberedheteroalkylene)-A², —(C₀₋₃ alkylene)-(C₃₋₆ cycloalkylene)-(C₀₋₃alkylene)-A², —O-A², —N(R⁸)-A², or -A²; wherein A² is a 5-6 memberedheterocyclic group containing at least one unsaturated carbon atom inthe ring and the heterocyclic group being optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and—N(R⁴)(R⁵); R^(2B) represents independently for each occurrence C₁₋₆alkyl or C₁₋₃ haloalkyl; R³ represents independently for each occurrencehydrogen, C₁₋₆ haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —O—(C₁₋₆ alkylene)-OH, or—O—(C₁₋₆ alkylene)-CO₂R⁴; or two vicinal occurrences of R³ are takentogether with intervening atoms to form a 4-6 membered ring; R⁴ and R⁵each represent independently for each occurrence hydrogen, C₁₋₆ alkyl,or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-7 membered heterocyclic ring; R⁶ and R⁷ eachrepresent independently for each occurrence hydrogen or C₁₋₆ alkyl, orR⁶ and R⁷ are taken together with the carbon atom to which they areattached to form a 3-6 membered carbocyclic ring; or R⁶ and R^(2A) aretaken together to form a bond; R⁸ represents independently for eachoccurrence hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or aralkyl; R⁹represents independently for each occurrence C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl; X is one of the following: (i) —(C₂₋₆alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl, —(C₁₋₆alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), -(5-6membered heterocycloalkylene)-phenyl, or —(C₃₋₆ cycloalkylene)-phenyl,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano; (ii) —(C₂₋₆ alkenylene)-(C₃₋₆ cycloalkyl),

or an 8-10 membered, bicyclic partially saturated carbocyclyl, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturatedcarbocyclic or heterocyclic ring; (iii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano; or (iv)—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partiallyunsaturated bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆cycloalkyl), each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, hydroxyl, and cyano; Y is —C(R⁶)(R⁷)—, —O—, —C(O)—, or—S(O)_(p)—; m and p each represent independently for each occurrence 0,1, or 2; and n is 1, 2, or
 3. 2. The compound of claim 1, wherein A¹ isphenylene or 5-6 membered heteroarylene.
 3. The compound of claim 1 or2, wherein R¹ represents independently for each occurrence halogen orC₁₋₆ alkyl.
 4. The compound of claim 1, wherein the compound isrepresented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is phenyleneor a 5-6 membered heteroarylene; R¹ represents independently for eachoccurrence halogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; R^(2A) is —(C₁₋₆alkylene)-A², -(2-6 membered heteroalkylene)-A², or —O-A²; wherein A² isa 5-6 membered heterocyclic group containing at least one unsaturatedcarbon atom in the ring and the heterocyclic group being optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵); R^(2B) representsindependently for each occurrence C₁₋₆ alkyl or C₁₋₃ haloalkyl; R³represents independently for each occurrence hydrogen, C₁₋₆ haloalkyl,halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or —O—(C₁₋₆ alkylene)-OH; or two vicinal occurrences of R³are taken together with intervening atoms to form a 4-6 membered ring;R⁴ and R⁵ each represent independently for each occurrence hydrogen,C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence of R⁴ and R⁵ attachedto the same nitrogen atom are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring; R⁶ andR⁷ each represent independently for each occurrence hydrogen or C₁₋₆alkyl, or R⁶ and R⁷ are taken together with the carbon atom to whichthey are attached to form a 3-6 membered carbocyclic ring; R⁸ representsindependently for each occurrence hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,or aralkyl; R⁹ represents independently for each occurrence C₁₋₆ alkyl,C₃₋₆ cycloalkyl, or aralkyl; X is one of the following: (i) —(C₂₋₆alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl, —(C₁₋₆alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6membered heterocycloalkylene)-phenyl, each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; (ii) —(C₁₋₆ alkylene)-Z¹or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl,—O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicycliccarbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or (iii)—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; Y is—C(R⁶)(R⁷)—, —O—, or —C(O)—; m and p are independently 0, 1, or 2; and nis 1, 2, or
 3. 5. The compound of any one of claims 1-4, wherein A¹ isphenylene.
 6. The compound of any one of claims 1-4, wherein A¹ is a 5-6membered heteroarylene.
 7. The compound of any one of claims 1-6,wherein n is
 1. 8. The compound of any one of claims 1-6, wherein n is 1or
 2. 9. The compound of any one of claims 1-8, wherein R³ representsindependently for each occurrence C₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —O—(C₁₋₆ alkylene)-OH.
 10. The compound of any one ofclaims 1-8, wherein R³ is trifluoromethyl, fluoro, chloro, or methoxy.11. The compound of any one of claims 1-8, wherein R³ istrifluoromethyl.
 12. The compound of claim 1 or 4, wherein -A¹-(R³)_(n)is


13. The compound of any one of claims 1-12, wherein R^(2A) is —(C₁₋₆alkylene)-A².
 14. The compound of any one of claims 1-12, wherein R^(2A)is —(C₂₋₃ alkylene)-A².
 15. The compound of any one of claims 1-12,wherein R^(2A) is -(2-6 membered heteroalkylene)-A².
 16. The compound ofany one of claims 1-12, wherein R^(2A) is —(C₂₋₃ alkylene)-O-A².
 17. Thecompound of any one of claims 1-12, wherein R^(2A) is —O-A²
 18. Thecompound of any one of claims 1-17, wherein A² comprises at least tworing nitrogen atoms.
 19. The compound of any one of claims 1-17, whereinA² comprises at least two ring nitrogen atoms, and at least one ringoxygen atom.
 20. The compound of any one of claims 1-19, wherein A² is a5-6 membered heterocyclic group containing at least one ring carbon atomsubstituted by oxo and the heterocyclic group being optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵),—N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 21. The compound of any one of claims1-19, wherein A² is a 5-6 membered heterocyclic group containing (i) atleast one ring carbon atom substituted by oxo and (ii) at least onedouble bond between two ring atoms, and the heterocyclic group beingoptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 22. The compound of anyone of claims 1-21, wherein the heterocyclic group in A² is a 5-memberedheterocyclic group.
 23. The compound of any one of claims 1-19, whereinA² is a 5-6 membered heteroaromatic group comprising at least two ringnitrogen atoms, at least one unsaturated carbon atom in the ring, andthe heteroaromatic group being optionally substituted by 1 or 2substituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and—N(R⁴)(R⁵).
 24. The compound of claim 23, wherein the heteroaromaticgroup in A² is a 5-membered heteroaromatic group.
 25. The compound ofany one of claims 1-17, wherein A² is imidazolyl; pyrazolyl;1,2,3-triazolyl; tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl;1,3,4-oxadiazol-2(3H)-onyl; 1,3-dihydro-2H-imidazol-2-onyl; or2,4-dihydro-3H-1,2,4-triazol-3-onyl; each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵),—N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 26. The compound of any one of claims1-17, wherein A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).
 27. The compound of any one ofclaims 1-17, wherein A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 28. The compound of anyone of claims 1-17, wherein A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).
 29. The compound of any one ofclaims 1-28, wherein R^(2B) is methyl.
 30. The compound of any one ofclaims 1-29, wherein X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy.
 31. The compound of any one of claims 1-29, wherein X is—(C₂₋₆ alkenylene)-phenyl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.
 32. The compound of any one of claims 1-29, wherein Xis —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹ is—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partiallyunsaturated bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆cycloalkyl), each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.
 33. The compound of any one of claims 1-29, wherein Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy.
 34. Thecompound of any one of claims 1-29, wherein X is —O—(C₁₋₆alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which issubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy.
 35. The compound of anyone of claims 1-34, wherein Y is —C(R⁶)(R⁷)—.
 36. The compound of anyone of claims 1-35, wherein R⁶ and R⁷ are independently hydrogen ormethyl.
 37. The compound of any one of claims 1-34, wherein Y is—C(R⁶)(R⁷)—, R⁶ and R⁷ are independently hydrogen or methyl, and X isattached at the 7-position of the 1,2,3,4-tetrahydroquinolinyl ring. 38.The compound of any one of claims 1-34, wherein Y is —O—.
 39. Thecompound of claim 38, wherein X is attached at the 6-position of the3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.
 40. The compound of any oneof claims 1-39, wherein m is 0 or
 1. 41. The compound of any one ofclaims 1-40, wherein p is
 0. 42. The compound of any one of claims 1-40,wherein p is
 1. 43. A compound represented by Formula II:

or a pharmaceutically acceptable salt thereof; wherein: A¹ is phenyl,5-6 membered heteroaryl, or C₃₋₆ heterocycloalkyl; R¹ representsindependently for each occurrence halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C₃₋₆ cycloalkyl; R^(2A) is —(C₁₋₆ alkylene)-A², -(2-6 memberedheteroalkylene)-A², —(C₀₋₃ alkylene)-(C₃₋₆ cycloalkylene)-(C₀₋₃alkylene)-A², —O-A², —N(R⁸)-A², or -A²; wherein A² is a 5-6 memberedheterocyclic group containing at least one unsaturated carbon atom inthe ring and the heterocyclic group being optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and—N(R⁴)(R⁵); R^(2B) represents independently for each occurrence C₁₋₆alkyl or C₁₋₃ haloalkyl; R^(2C) is hydrogen or C₁₋₆ alkyl; R³ representsindependently for each occurrence hydrogen, C₁₋₆ haloalkyl, halogen,hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—O—(C₁₋₆ alkylene)-OH, or —O—(C₁₋₆ alkylene)-CO₂R⁴; or two vicinaloccurrences of R³ are taken together with intervening atoms to form a4-6 membered ring; R⁴ and R⁵ each represent independently for eachoccurrence hydrogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or an occurrence ofR⁴ and R⁵ attached to the same nitrogen atom are taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocyclic ring; R⁶ and R⁷ each represent independently for eachoccurrence hydrogen or C₁₋₆ alkyl, or R⁶ and R⁷ are taken together withthe carbon atom to which they are attached to form a 3-6 memberedcarbocyclic ring; or R⁶ and R^(2A) are taken together to form a bond; R⁸represents independently for each occurrence hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, or aralkyl; R⁹ represents independently for each occurrenceC₁₋₆ alkyl, C₃₋₆ cycloalkyl, or aralkyl; X is one of the following: (i)—(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆ alkenylene)-heteroaryl, —(C₁₋₆alkylene)-phenyl, —(C₁₋₆ alkylene)-heteroaryl, —(C₁₋₆alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C₁₋₆alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), -(5-6membered heterocycloalkylene)-phenyl, or —(C₃₋₆ cycloalkylene)-phenyl,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano; (ii) —(C₂₋₆ alkenylene)-(C₃₋₆ cycloalkyl),

or an 8-10 membered, bicyclic partially saturated carbocyclyl, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturatedcarbocyclic or heterocyclic ring; (iii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano; or (iv)—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partiallyunsaturated bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆cycloalkyl), each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, hydroxyl, and cyano; Y is —C(R⁶)(R⁷)—, —O—, —C(O)—, or—S(O)_(p)—; m and p each represent independently for each occurrence 0,1, or 2; and n is 0, 1, 2, or
 3. 44. The compound of claim 43, whereinA¹ is phenylene or 5-6 membered heteroarylene.
 45. The compound of claim43 or 44, wherein R¹ represents independently for each occurrencehalogen or C₁₋₆ alkyl.
 46. The compound of claim 43, wherein thecompound is represented by Formula II-A:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is phenyleneor a 5-6 membered heteroarylene; R¹ represents independently for eachoccurrence halogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; R^(2A) is —(C₁₋₆alkylene)-A², -(2-6 membered heteroalkylene)-A², or —O-A²; wherein A² isa 5-6 membered heterocyclic group containing at least one unsaturatedcarbon atom in the ring and the heterocyclic group being optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵); R^(2B) representsindependently for each occurrence C₁₋₆ alkyl or C₁₋₃ haloalkyl; R^(2C)is hydrogen or C₁₋₆ alkyl; R³ represents independently for eachoccurrence hydrogen, C₁₋₆ haloalkyl, halogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or —O—(C₁₋₆ alkylene)-OH; ortwo vicinal occurrences of R³ are taken together with intervening atomsto form a 4-6 membered ring; R⁴ and R⁵ each represent independently foreach occurrence hydrogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; or anoccurrence of R⁴ and R⁵ attached to the same nitrogen atom are takentogether with the nitrogen atom to which they are attached to form a 3-7membered heterocyclic ring; R⁶ and R⁷ each represent independently foreach occurrence hydrogen or C₁₋₆ alkyl, or R⁶ and R⁷ are taken togetherwith the carbon atom to which they are attached to form a 3-6 memberedcarbocyclic ring; R⁸ represents independently for each occurrencehydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or aralkyl; R⁹ representsindependently for each occurrence C₁₋₆ alkyl, C₃₋₆ cycloalkyl, oraralkyl; X is one of the following: (i) —(C₂₋₆ alkenylene)-phenyl,—(C₂₋₆ alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C₃₋₆cycloalkylene)-phenyl, each of which is optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, hydroxyl, and cyano; (ii) —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆alkenylene)-Z¹, wherein Z¹ is —O-aralkyl, —O-heteroaralkyl, —O-phenyl,—O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C₁₋₆alkylene)-(C₃₋₆ cycloalkyl), —O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl,—N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicyclic carbocyclyl), or—N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, hydroxyl, and cyano; or (iii)—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partiallyunsaturated bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆cycloalkyl), each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, hydroxyl, and cyano; Y is —C(R⁶)(R⁷)—, —O—, or —C(O)—; m andp are independently 0, 1, or 2; and n is 1, 2, or
 3. 47. The compound ofany one of claims 43-46, wherein A¹ is phenylene.
 48. The compound ofany one of claims 43-46, wherein A¹ is a 5-6 membered heteroarylene. 49.The compound of any one of claims 43-48, wherein n is
 1. 50. Thecompound of any one of claims 43-48, wherein n is 1 or
 2. 51. Thecompound of any one of claims 43-50, wherein R³ represents independentlyfor each occurrence C₁₋₆ haloalkyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or—O—(C₁₋₆ alkylene)-OH.
 52. The compound of any one of claims 43-50,wherein R³ is trifluoromethyl, fluoro, chloro, or methoxy.
 53. Thecompound of any one of claims 43-50, wherein R³ is trifluoromethyl. 54.The compound of claim 43 or 46, wherein -A¹-(R³)_(n) is


55. The compound of any one of claims 43-54, wherein R^(2A) is —(C₁₋₆alkylene)-A².
 56. The compound of any one of claims 43-54, whereinR^(2A) is —(C₂₋₃ alkylene)-A².
 57. The compound of any one of claims43-54, wherein R^(2A) is -(2-6 membered heteroalkylene)-A².
 58. Thecompound of any one of claims 43-54, wherein R^(2A) is —(C₂-3alkylene)-O-A².
 59. The compound of any one of claims 43-54, whereinR^(2A) is —O-A².
 60. The compound of any one of claims 43-59, wherein A²comprises at least two ring nitrogen atoms.
 61. The compound of any oneof claims 43-59, wherein A² comprises at least two ring nitrogen atoms,and at least one ring oxygen atom.
 62. The compound of any one of claims43-61, wherein A² is a 5-6 membered heterocyclic group containing atleast one ring carbon atom substituted by oxo and the heterocyclic groupbeing optionally substituted by 1 or 2 substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 63. The compound of anyone of claims 43-61, wherein A² is a 5-6 membered heterocyclic groupcontaining (i) at least one ring carbon atom substituted by oxo and (ii)at least one double bond between two ring atoms, and the heterocyclicgroup being optionally substituted by 1 or 2 substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, oxo, —C(O)R⁹, —CO₂R,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 64. The compound of anyone of claims 43-63, wherein the heterocyclic group in A² is a5-membered heterocyclic group.
 65. The compound of any one of claims43-61, wherein A² is a 5-6 membered heteroaromatic group comprising atleast two ring nitrogen atoms, at least one unsaturated carbon atom inthe ring, and the heteroaromatic group being optionally substituted by 1or 2 substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and—N(R⁴)(R⁵).
 66. The compound of claim 65, wherein the heteroaromaticgroup in A² is a 5-membered heteroaromatic group.
 67. The compound ofany one of claims 43-59, wherein A² is imidazolyl; pyrazolyl;1,2,3-triazolyl; tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl;1,3,4-oxadiazol-2(3H)-onyl; 1,3-dihydro-2H-imidazol-2-onyl; or2,4-dihydro-3H-1,2,4-triazol-3-onyl; each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸, —C(O)(N⁴)(R⁵),—N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 68. The compound of any one of claims43-59, wherein A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).
 69. The compound of any one ofclaims 43-59, wherein A² is oxazolidin-2-onyl; oxazolidine-2,4-dionyl;imidazolidine-2,4-dionyl; or thiazolidine-2,4-dionyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —C(O)R⁹, —CO₂R⁸,—C(O)(N⁴)(R⁵), —N(R⁴)C(O)(R⁹), and —N(R⁴)(R⁵).
 70. The compound of anyone of claims 43-59, wherein A² is one of the following:

each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—C(O)R⁹, —CO₂R⁸, and —C(O)(N⁴)(R⁵).
 71. The compound of any one ofclaims 43-70, wherein R^(2B) is methyl.
 72. The compound of any one ofclaims 43-71, wherein X is —(C₂₋₆ alkenylene)-phenyl, —(C₂₋₆alkenylene)-heteroaryl, —(C₁₋₆ alkylene)-phenyl, —(C₁₋₆alkylene)-heteroaryl, —(C₁₋₆ alkylene)-(partially unsaturated bicyclicheterocyclyl), —(C₁₋₆ alkylene)-(partially unsaturated bicyclicoxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy.
 73. The compound of any one of claims 43-71, wherein X is—(C₂₋₆ alkenylene)-phenyl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.
 74. The compound of any one of claims 43-71, wherein Xis —(C₁₋₆ alkylene)-Z¹ or —(C₂₋₆ alkenylene)-Z¹, wherein Z¹ is—O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—O—(C₃₋₆ cycloalkyl), —N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partiallyunsaturated bicyclic carbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆cycloalkyl), each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.
 75. The compound of any one of claims 43-71, wherein Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partiallyunsaturated bicyclic carbocyclyl), —O—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl),—N(R⁴)-aralkyl, —N(R⁴)-phenyl, —N(R⁴)-(partially unsaturated bicycliccarbocyclyl), or —N(R⁴)—(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy.
 76. Thecompound of any one of claims 43-71, wherein X is —O—(C₁₋₆alkylene)-phenyl or —N(R⁴)—(C₁₋₆ alkylene)-phenyl, each of which issubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy.
 77. The compound of anyone of claims 43-76, wherein Y is —C(R⁶)(R⁷)—.
 78. The compound of anyone of claims 43-77, wherein R⁶ and R⁷ are independently hydrogen ormethyl.
 79. The compound of any one of claims 43-76, wherein Y is—C(R⁶)(R⁷)—, R⁶ and R⁷ are independently hydrogen or methyl, and X isattached at the 7-position of the 1,2,3,4-tetrahydronaphthalenyl ring.80. The compound of any one of claims 43-76, wherein Y is —O—.
 81. Thecompound of claim 80, wherein X is attached at the 6-position of thechromanyl ring.
 82. The compound of any one of claims 43-81, wherein mis 0 or
 1. 83. The compound of any one of claims 43-82, wherein p is 0.84. The compound of any one of claims 43-82, wherein p is
 1. 85. Acompound represented by Formula I-C:

or a pharmaceutically acceptable salt thereof; wherein: A¹ is phenyleneor pyrazolylene; R^(2A) is -(2-6 membered heteroalkylene)-A²; wherein A²is a 5-6 membered heterocyclic group containing at least one unsaturatedcarbon atom and the heterocyclic group being optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, chloro, fluoro, and oxo; R³ representsindependently for each occurrence C₁₋₂ fluoroalkyl, chloro, fluoro,cyclopropyl, C₁₋₃ alkyl, C₁₋₂ alkoxy, or C₁₋₂ fluoroalkoxy; X is —(C₂₋₆alkenylene)-phenyl wherein the phenyl is substituted with 1, 2, or 3substituents independently selected from the group consisting of chloro,fluoro, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, and C₁₋₂ fluoroalkoxy; n is 1 or2.
 86. The compound of claim 85, wherein A¹ is phenylene; and R³represents independently for each occurrence C₁₋₂ fluoroalkyl, chloro,fluoro, C₁₋₂ alkoxy, or C₁₋₂ fluoroalkoxy.
 87. The compound of claim 85or 86, wherein R^(2A) is (C₂₋₃ alkylene)-O-A².
 88. The compound of claim85 or 86, wherein R^(2A) is —(CH₂)₂-O-A².
 89. The compound of any one ofclaims 85-88, wherein A² is


90. The compound of any one of claims 85-89, wherein X is—(C(H)═C(CH₃))-phenyl substituted with 1 or 2 substituents independentlyselected from the group consisting of chloro, fluoro, andtrifluoromethyl, and said substituents are located at the orthopositions of the phenyl group.
 91. A compound in any one of Tables 1-8herein or a pharmaceutically acceptable salt thereof.
 92. Apharmaceutical composition comprising a compound of any one of claims1-91 and a pharmaceutically acceptable carrier.
 93. A method of treatinga disorder selected from the group consisting of cancer, bacterialinfection, fungal infection, and immune deficiency disorder, comprisingadministering a therapeutically effective amount of a compound of anyone of claims 1-91 to a subject in need thereof to ameliorate a symptomof the disorder.
 94. The method of claim 93, wherein the disorder iscancer.
 95. The method of claim 93, wherein the disorder is coloncancer, pancreatic cancer, breast cancer, ovarian cancer, prostatecancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma,sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia,bladder cancer, stomach cancer, cervical cancer, testicular cancer, skincancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer,espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma,meningioma, neuroblastoma, or retinoblastoma.
 96. A method of increasingthe amount of IL-17 in a subject, comprising administering to a subjectan effective amount of a compound of any one of claims 1-91 to increasethe amount of IL-17 in the subject.
 97. The method of any one of claims93-96, wherein the subject is a human.
 98. A method of promoting theactivity of RORγ, comprising exposing a RORγ to an effective amount of acompound of any one of claims 1-91 to promote the activity of said RORγ.